A Phase II Study of Navarixin (MK-7123) in Combination With Pembrolizumab (MK-3475) in Participants With Selected Advanced/Metastatic Solid Tumors
Phase: PHASE2
Conditions: Solid Tumors, Non-small Cell Lung Cancer, Castration Resistant Prostate Cancer, Microsatellite Stable Colorectal Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Phase II Study of Navarixin (MK-7123) in Combination 
with Pembrolizumab (MK-3475) in Participants with Selected 
Advanced/Metastatic Solid Tumors
22-March-2018
NCT03473925

Product:  MK-7123 SCH 527123
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Protocol/Amendment No.: 034-01 
MK-7123-034-01 Final Protocol
22-Mar-2018
Confidential
Title Page
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., NJ, U.S.A.
(MSD).
Protocol Title: A Phase II Study of Navarixin (MK-7123) in Combination with 
Pembrolizumab (MK-3475) in Participants with Selected Advanced/Metastatic Solid Tumors
Protocol Number: 034-01
Compound Number: MK-7123
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or MSD)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER:   137,203
EudraCT NUMBER: Not Applicable
Approval Date:  22-Mar-2018
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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Protocol/Amendment No.: 034-01 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 01
Overall Rationale for the Amendment:
Revisions/updates incorporated based on feedback from regulatory agency, data management, and sites.
Summary of Changes Table:
Section # and
Name
Description of Change
Brief Rationale
2. Schedule of 
Activities (SoA)
Addition of row in Efficacy Procedures 
section for MSI testing of tumor sample in 
participants with CRPC who show a 
response to treatment
To assist in interpreting response to treatment in the CRPC 
participant population.
9.2.3 MSI Status
Information noting that MSI testing will be 
performed on tumor samples from CRPC 
participants who show a response to 
treatment
To align with the change made to the Schedule of Activities 
described in the row above.
(To assist in interpreting response to treatment in the CRPC 
participant population)
2. Schedule of 
Activities (SoA)
In Notes cell of Hematology row:
Revision of description of time points for 
collection of hematology (including ANC) 
blood samples.
This change is made to remove ambiguity regarding collection of 
ANC samples:

As a safety lab, hematology (including ANC) will be collected 
on Day 1 of every cycle pre-dose as follows:

On days when navarixin PK samples are collected, 
pre-dose ANC should be collected within 2 hours prior 
to dosing.

On days when navarixin PK is not collected, pre-dose 
ANC can be collected within 24 hours prior to dosing

An additional sample (for pharmacodynamics assessment)
will be collected between 6-12 hours after dosing on Days 1, 
3, and 8 of Cycle 1, and Day 1 of Cycle 2.
 
 
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Section # and
Name
Description of Change
Brief Rationale
9.7 
Pharmacodynamics
Removal of the phrase “After Cycle 4: 
Same scheme as Pembro PK” from 
description of when venous samples for 
ANC are to be collected.
To align with the change made to the Schedule of Activities 
described in the row above.
(To remove ambiguity regarding collection of ANC samples)
2. Schedule of 
Activities (SoA)
In Notes cell of Comprehensive Chemistry 
Panel row:
Revision of description of time points for 
collection of chemistry panel blood 
samples.
The following change is made to allow chemistry samples to be 
collected at the same time as hematology samples:

Chemistry panel will be collected on Day 1 of every cycle 
pre-dose as follows:

On days when navarixin PK samples are collected, pre-
dose sample should be collected within 2 hours prior to 
dosing.

On days when navarixin PK is not collected, pre-dose 
sample can be collected within 24 hours prior to dosing.
2. Schedule of 
Activities (SoA)
In Notes cell of Thyroid Function (T3, or 
FT3, T4 or  FT4, and TSH) Testing row:
Revision of description of time points for 
collection of thyroid testing blood samples.
The following change is made to allow thyroid function samples 
to be collected at the same time as hematology samples:

Thyroid testing will be collected on Day 1 of every cycle pre-
dose as follows:

On days when navarixin PK samples are collected, pre-
dose sample should be collected within 2 hours prior to 
dosing.

On days when navarixin PK is not collected, pre-dose 
sample can be collected within 24 hours prior to dosing.
 
 
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Section # and
Name
Description of Change
Brief Rationale
5.1 Overall Design
Added clarifying language regarding 
discontinuing enrollment in an arm due to 
DLTs in Stage 1.
The following sentence is added to ensure participant safety:
However, during Stage 1, if at any time >3 DLTs are observed 
within the first 10 evaluable participants, enrollment into an 
arm will be discontinued. 
5.1 Overall Design
Stopping rule for excessive toxicity 
occurring outside the protocol defined 
window is added.
This change is made to ensure participant safety.
5.1.3 Dose 
Limiting Toxicity
Definition of DLT is modified.
The following criteria for anemia are added to expand the 
definition of DLT:

Grade 4 anemia of any duration

Grade 3 anemia lasting >7 days or requiring transfusion
6.1 Exclusion 
Criteria
Exclusion Criterion #4 is modified, adding 
the sentence
“In addition to active autoimmune disease, 
participants who have previously been 
permanently discontinued from PD-(L)1 
therapy due to immune related side effects 
are not eligible for the study.”
This change is made for participant safety.
6.1 Exclusion 
Criteria
Exclusion criterion #5, “History of 
vasculitis” is deleted.
(list of criteria has been renumbered)
Vasculitis is not a risk for navarixin or pembrolizumab.
 
 
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Section # and
Name
Description of Change
Brief Rationale
6.1 Exclusion 
Criteria
Exclusion criterion #12 (previously
criterion #13) is modified to include 
history or evidence of gastrointestinal 
condition(s) or impaired liver function or 
diseases that may significantly alter 
absorption or metabolism of oral 
medication.
This change is made because navarixin is administered orally.
9.1.12 Calibration 
of Equipment
Bulleted list of critical equipment for the 
trial is deleted.
This change is made per process update. 
9.2.1.3 End of 
Treatment and 
Follow-up Tumor 
Imaging
Monitoring 
disease 
status 
by 
tumor 
imaging is changed from every 9 weeks to 
every 12 weeks (±7 days).
This change corrects the end of treatment and follow-up tumor 
imaging interval to be consistent with that shown in the Schedule 
of Activities.
9.3.1  Time Period 
and Frequency for 
Collecting AE, 
SAE and Other 
Reportable Safety 
Event Information 
The time period and frequency for 
collection of AE, SAE and other reportable 
safety event information is corrected.
This correction ensures alignment of the time period and 
frequency of data collection with pembrolizumab protocol 
standards and is consistent with other sections of the protocol.
 
 
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Table of Contents
PROTOCOL AMENDMENT SUMMARY OF CHANGES ...............................................3
1.
Synopsis.......................................................................................................................15
2.
Schedule of Activities (SoA) ......................................................................................19
3.
Introduction................................................................................................................29
Study Rationale .......................................................................................................29
3.1
Background..............................................................................................................29
3.2
Pharmaceutical and Therapeutic Background .....................................................30
3.2.1
Navarixin Pharmaceutical and Therapeutic Background .............................30
3.2.1.1
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic 
3.2.1.2
Background...................................................................................................31
Benefit/Risk Assessment.........................................................................................31
3.3
4.
Objectives/Hypotheses and Endpoints.....................................................................32
5.
Study Design...............................................................................................................33
Overall Design .........................................................................................................33
5.1
Study Diagram .....................................................................................................35
5.1.1
Evaluation of Safety.............................................................................................36
5.1.2
Dose Limiting Toxicity........................................................................................37
5.1.3
Futility Analysis...................................................................................................38
5.1.4
Number of Participants ..........................................................................................38
5.2
Beginning and End of Study Definition ................................................................38
5.3
Clinical Criteria for Early Study Termination .....................................................39
5.3.1
Scientific Rationale for Study Design....................................................................39
5.4
Rationale for Endpoints .......................................................................................39
5.4.1
Efficacy Endpoints......................................................................................39
5.4.1.1
Safety Endpoints ...........................................................................................40
5.4.1.2
Pharmacokinetic Endpoints ..........................................................................40
5.4.1.3
Pharmacodynamic Endpoints........................................................................40
5.4.1.4
Planned Exploratory Biomarker Research....................................................41
5.4.1.5
 
 
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Planned Genetic Analysis ......................................................................42
5.4.1.5.1
Future Biomedical Research.........................................................................42
5.4.1.6
Justification for Dose ..............................................................................................43
5.5
Starting Dose for This Study................................................................................43
5.5.1
Maximum Dose/Exposure for This Study ...........................................................44
5.5.2
Rationale for Dose Interval and Study Design.....................................................44
5.5.3
6.
Study Population........................................................................................................45
Inclusion Criteria ....................................................................................................45
6.1
Exclusion Criteria ...................................................................................................49
6.2
Lifestyle Restrictions...............................................................................................51
6.3
Screen Failures ........................................................................................................51
6.4
Participant Replacement Strategy.........................................................................51
6.5
7.
Treatments..................................................................................................................52
Treatments Administered.......................................................................................52
7.1
Dose Modification ...................................................................................................53
7.2
Navarixin Dose Modification ..............................................................................53
7.2.1
Pembrolizumab Dose Modification .....................................................................56
7.2.2
Method of Treatment Assignment.........................................................................61
7.3
Stratification.........................................................................................................61
7.3.1
Blinding....................................................................................................................61
7.4
Preparation/Handling/Storage/Accountability ....................................................61
7.5
Dose Preparation..................................................................................................61
7.5.1
Handling, Storage and Accountability.................................................................61
7.5.2
Treatment Compliance...........................................................................................62
7.6
Concomitant Therapy.............................................................................................62
7.7
Rescue Medications and Supportive Care ...........................................................62
7.7.1
Treatment After the End of the Study ..................................................................67
7.8
Clinical Supplies Disclosure ...................................................................................67
7.9
8.
Discontinuation/Withdrawal Criteria......................................................................67
Discontinuation of Study Treatment .....................................................................67
8.1
Withdrawal from the Study ...................................................................................67
8.2
 
 
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Lost to Follow Up ....................................................................................................68
8.3
9.
Study Assessments and Procedures..........................................................................68
Administrative and General Procedures ..............................................................69
9.1
Informed Consent.................................................................................................69
9.1.1
General Informed Consent............................................................................69
9.1.1.1
Consent and Collection of Specimens for Future Biomedical 
9.1.1.2
Research........................................................................................................70
Inclusion/Exclusion Criteria ................................................................................70
9.1.2
Participant Identification Card.............................................................................70
9.1.3
Medical History ...................................................................................................70
9.1.4
General Medical History...............................................................................70
9.1.4.1
Oncologic Disease Details ............................................................................70
9.1.4.2
Prior and Concomitant Medications Review .......................................................71
9.1.5
Prior Medications..........................................................................................71
9.1.5.1
Prior Oncologic Treatment ...........................................................................71
9.1.5.2
Concomitant Medications .............................................................................71
9.1.5.3
Assignment of Screening Number .......................................................................71
9.1.6
Assignment of Treatment/Randomization Number .............................................71
9.1.7
Treatment Administration....................................................................................72
9.1.8
Timing of Dose Administration....................................................................72
9.1.8.1
Discontinuation and Withdrawal .........................................................................72
9.1.9
Withdrawal From Future Biomedical Research ...........................................72
9.1.9.1
Participant Blinding/Unblinding..........................................................................72
9.1.10
Domiciling ...........................................................................................................72
9.1.11
Calibration of Equipment.....................................................................................73
9.1.12
Efficacy Assessments...............................................................................................73
9.2
Tumor Imaging and Assessment of Disease ........................................................73
9.2.1
Initial Tumor Imaging...................................................................................73
9.2.1.1
Tumor Imaging During the Study.................................................................74
9.2.1.2
End of Treatment and Follow-up Tumor Imaging........................................74
9.2.1.3
RECIST 1.1 Assessment of Disease .............................................................74
9.2.1.4
iRECIST Assessment of Disease ..................................................................75
9.2.1.5
 
 
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Prostate-Specific Antigen ....................................................................................77
9.2.2
MSI Status in CPRC Patients...............................................................................77
9.2.3
Adverse Events (AE), Serious Adverse Events (SAE) and Other Reportable 
9.3
Safety Events ...........................................................................................................77
Time Period and Frequency for Collecting AE, SAE and Other 
9.3.1
Reportable Safety Event Information ..................................................................78
Method of Detecting AE, SAE and Other Reportable Safety Events ..................80
9.3.2
Follow-up of AE, SAE and Other Reportable Safety Event Information............80
9.3.3
Regulatory Reporting Requirements for SAE .....................................................80
9.3.4
Disease-Related Events and/or Disease-Related Outcomes Not 
9.3.5
Qualifying as AEs or SAEs..................................................................................80
Pregnancy and Exposure During Breastfeeding ..................................................81
9.3.6
Events of Clinical Interest (ECI)..........................................................................81
9.3.7
Treatment of Overdose...........................................................................................81
9.4
Safety........................................................................................................................81
9.5
Physical Examinations .........................................................................................82
9.5.1
Full Physical Exam .......................................................................................82
9.5.1.1
Directed Physical Exam.........................................................................82
9.5.1.1.1
Vital Signs............................................................................................................82
9.5.2
Electrocardiograms ..............................................................................................82
9.5.3
Clinical Safety Laboratory Assessments..............................................................82
9.5.4
Pharmacokinetics....................................................................................................83
9.6
Blood Collection for Plasma Navarixin...............................................................83
9.6.1
Cycle 1 ..........................................................................................................83
9.6.1.1
Cycles 2 to 4..................................................................................................83
9.6.1.2
After Cycle 4.................................................................................................84
9.6.1.3
Blood Collection for Pembrolizumab ..................................................................84
9.6.2
Pharmacodynamics.................................................................................................84
9.7
Biomarkers ..............................................................................................................84
9.8
Future Biomedical Research Sample Collection ..................................................85
9.9
Health Economics....................................................................................................85
9.10
Visit Requirements..................................................................................................85
9.11
Screening..............................................................................................................85
9.11.1
 
 
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Treatment Period..................................................................................................86
9.11.2
Post-Study............................................................................................................86
9.11.3
Safety Follow-up Visit..................................................................................86
9.11.3.1
Disease Status Follow-up..............................................................................86
9.11.3.2
Survival Follow-up .......................................................................................86
9.11.3.3
Survival Status .....................................................................................................87
9.11.4
10.
Statistical Analysis Plan ............................................................................................87
Statistical Analysis Plan Summary........................................................................87
10.1
Responsibility for Analyses/In-House Blinding....................................................89
10.2
Hypotheses/Estimation ...........................................................................................89
10.3
Analysis Endpoints..................................................................................................89
10.4
Efficacy/Pharmacokinetics/Pharmacodynamic Endpoints ..................................89
10.4.1
Safety Endpoints ..................................................................................................90
10.4.2
Analysis Populations...............................................................................................90
10.5
Efficacy Analysis Populations .............................................................................90
10.5.1
Safety Analysis Populations ................................................................................90
10.5.2
Pharmacokinetic Analysis Populations................................................................90
10.5.3
Statistical Methods..................................................................................................90
10.6
Statistical Methods for Efficacy Analysis............................................................91
10.6.1
Statistical Methods for Safety Analysis ...............................................................91
10.6.2
Summaries of Baseline Characteristics, Demographics, and Other 
10.6.3
Analyses...............................................................................................................91
Demographic and Baseline Characteristics ..................................................91
10.6.3.1
Pharmacokinetic and Pharmacodynamic Modeling Analysis.......................91
10.6.3.2
Interim Analyses .....................................................................................................91
10.7
Multiplicity ..............................................................................................................92
10.8
Sample Size and Power Calculations ....................................................................92
10.9
Subgroup Analyses..................................................................................................93
10.10
Compliance (Medication Adherence)....................................................................93
10.11
Extent of Exposure..................................................................................................93
10.12
11.
References...................................................................................................................93
12.
Appendices..................................................................................................................96
 
 
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Appendix 1: Study Governance Considerations ..................................................96
12.1
Merck Code of Conduct for Clinical Trials .....................................................................96
Financial Disclosure.........................................................................................................98
Data Protection.................................................................................................................98
Confidentiality of Data ....................................................................................................98
Confidentiality of Participant Records.............................................................................98
Confidentiality of IRB/IEC Information..........................................................................99
Publication Policy ............................................................................................................99
Compliance with Study Registration and Results Posting Requirements .......................99
Compliance with Law, Audit and Debarment ...............................................................100
Data Quality Assurance .................................................................................................100
Source Documents .........................................................................................................101
Study and Site Closure...................................................................................................101
Appendix 2: Collection and Management of Specimens for Future 
12.2
Biomedical Research.............................................................................................102
Appendix 3: Contraceptive Guidance and Pregnancy Testing.........................106
12.3
Definitions......................................................................................................................106
Contraception Requirements..........................................................................................107
Pregnancy Testing..........................................................................................................109
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
12.4
Evaluating, Follow-up, and Reporting................................................................110
Definition of AE ............................................................................................................110
Definition of SAE ......................................................................................................111
Additional Events reported in the same manner as SAE ...............................................112
Recording AE and SAE .................................................................................................112
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor ................115
Appendix 5: Clinical Laboratory Tests...............................................................117
12.5
Appendix 6: Abbreviations and Trademarks.....................................................119
12.6
Appendix 7: Description of the iRECIST Process for Assessment of Disease 
12.7
Progression ............................................................................................................122
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values......................................................48
Table 2
Study Treatment(s) ...............................................................................................52
Table 3
Navarixin/Study Drug Dose Modifications..........................................................54
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab.......................................................57
Table 5
Pembrolizumab Infusion Reaction Treatment Guidelines....................................65
Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease..................................................................................................................76
Table 7
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................79
Table 8
Probability That ORR is Claimed as Clinical Interest With 20 
Participants in Each Tumor Type of Each Arm....................................................92
Table 9
The CI of the True ORR Under Different Hypothetical Number of 
Observed Response Scenarios With 20 Participants in Each Tumor 
Type of Each Arm ................................................................................................93
Table 10
Highly Effective Contraception Methods...........................................................108
Table 11
Protocol-Required Safety Laboratory Assessments ...........................................117
 
 
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LIST OF FIGURES
Figure 1
Study Design.........................................................................................................35
Figure 2
Guidance for Dose Decision and Expansion ........................................................36
Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigators..........................................................................................................77
 
 
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1. Synopsis
Protocol Title:  
A Phase II Study of Navarixin (MK-7123) in Combination with Pembrolizumab (MK-3475) in 
Participants with Selected Advanced/Metastatic Solid Tumors
Short Title: 
A Phase II Study of Navarixin (MK-7123) in Combination with Pembrolizumab (MK-3475) in 
Participants with Selected Advanced/Metastatic Solid Tumors
Objectives/Hypotheses and Endpoints:
Male/female participants of at least 18 years of age with selected advanced/metastatic solid 
tumors will be enrolled in this study.
Objective
Endpoint
Primary

Objective: To evaluate the objective 
response rate (ORR) as assessed by the 
investigator based on Response 
Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1) following 
administration of navarixin in 
combination with pembrolizumab. 

Objective response is a confirmed 
complete response (CR) or partial 
response (PR).

Objective: To determine the safety and 
tolerability of navarixin in combination 
with pembrolizumab.

Dose-limiting toxicity (DLT)

Adverse event (AE)

Discontinuing study treatment due to 
an AE.  
Secondary

Objective: To evaluate objective 
response rate (ORR) as assessed by 
investigator based on iRecist (modified 
RECIST 1.1), progression-free survival 
(PFS) as assessed by RECIST and 
iRECIST and overall survival (OS) 
following administration of navarixin 
in combination with pembrolizumab.

Objective response is a confirmed CR 
or PR.

PFS is time from the first dose of study 
medication to the first documented 
disease progression or death due to any 
cause, whichever occurs first.

OS is time from the first dose of study 
medication to death due to any cause.

Objective: To evaluate the 
pharmacodynamics as measured by 
absolute neutrophil counts (ANC) 
following administration of navarixin in 
combination with pembrolizumab.

ANC in 109/L
 
 
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
Objective: To evaluate the 
pharmacokinetics of navarixin when 
administered in combination with 
pembrolizumab.

Pharmacokinetic parameters including 
area under the curve (AUC) in 
ng·hr/mL, maximum concentration 
(Cmax) in ng/mL, trough concentration 
(Ctrough) in ng/mL
Overall Design:
Study Phase
Phase 2
Clinical Indication
Treatment of participants with advanced/metastatic solid 
tumors.
Population
Participants with histologically or cytologically confirmed 
advanced/metastatic solid tumors in 3 selected tumor types.
Study Type
Interventional
Type of Design
This is a stratified, parallel, 2-dose randomized (1:1), 
uncontrolled multicenter study of navarixin in combination 
with pembrolizumab. The study will use a 2-stage adaptive 
design based on pre-specified criteria for response rate.
Type of Control
  No treatment control
Study Blinding
Unblinded Open-label
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 3 years from the time the first participant signs 
the informed consent until the last participant’s last study-
related phone call or visit.  
 
 
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Number of Participants:
Approximately 120 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
Participants will be stratified by tumor type and randomized 
1:1 to either of 2 dose level arms: Arm A will receive 30 mg 
navarixin orally QD + pembrolizumab 200 mg IV Q3W; 
Arm B will receive 100 mg navarixin orally QD + 
pembrolizumab 200 mg IV Q3W.
In Stage 1 of the study, 30 participants will be randomized to 
each arm. In Stage 2, barring early termination of the arm, 30 
additional participants will be randomized to each arm.
Duration of 
Participation
Each participant will participate in the study from the time 
the participant signs the informed consent form (ICF) 
through the final protocol-specified contact.  
After a screening phase of up to 28 days, each participant 
will be assigned to receive study treatment until disease 
progression is radiographically documented and, when 
clinically appropriate, confirmed by the site per modified 
Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics (iRECIST), unacceptable adverse 
event(s) (AEs), intercurrent illness that prevents further 
administration of treatment, Investigator’s decision to 
withdraw the participant, noncompliance with study 
treatment or procedure requirements, administrative reasons 
requiring cessation of treatment, or until the participant has 
received 35 administrations (approximately 2 years) of
combination treatment with navarixin and pembrolizumab. 
Monotherapy treatment with pembrolizumab will be allowed 
if navarixin treatment is withheld for ANC or febrile 
neutropenia.  
After the end of treatment, each participant will be followed 
for the occurrence of AEs and spontaneously reported 
pregnancy as described under Section 9.3.  
Participants who discontinue for reasons other than 
radiographic disease progression will have post-treatment 
follow-up imaging for disease status until disease 
progression is documented radiographically per RECIST 1.1 
and, when clinically appropriate, confirmed by the site per 
iRECIST, initiating a non-study cancer treatment, 
withdrawing consent, becoming lost to follow-up or the end 
of the study.  All participants will be followed by telephone 
for overall survival until death, participant withdrawal of 
consent, becoming lost to follow-up or the end of the study.  
 
 
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Study governance considerations are outlined in Appendix 1. A list of abbreviations used in 
this document can be found in Appendix 6.
 
 
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2. Schedule of Activities (SoA)
Trial Period:
Screening 
Phase
Treatment Phase  (21-day Treatment 
Cycles)
End of 
Treatment 
(EOT) / 
Discon-
tinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety Follow-
up
Imaging 
Follow-
up
Survival 
Follow-up
Treatment Days per 
Cycle:
1
3
8
1
1
1
At time of 
treatment 
discon.
30 days post 
last dose study 
medication
Every 12 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
± 3
± 3
± 3
+7
+7
± 7
± 7
Procedure windows may vary 
Administrative Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research
X
Participant Identification 
Card
X
Inclusion/Exclusion 
Criteria
X
Demographic and 
Medical History 
X
Oncology Disease Details 
and Prior Oncology 
Treatment History
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
Treatment 
Randomization
X
Dose within 3 days of 
randomization  
 
 
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Trial Period:
Screening 
Phase
Treatment Phase  (21-day Treatment 
Cycles)
End of 
Treatment 
(EOT) / 
Discon-
tinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety Follow-
up
Imaging 
Follow-
up
Survival 
Follow-up
Treatment Days per 
Cycle:
1
3
8
1
1
1
At time of 
treatment 
discon.
30 days post 
last dose study 
medication
Every 12 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
± 3
± 3
± 3
+7
+7
± 7
± 7
Procedure windows may vary 
Navarixin
Administration
Navarixin doses:
Arm A: 30 mg orally QD
or
Arm B: 100 mg orally QD
Pembrolizumab 
Administration  
X
X
X
X
Pembrolizumab dose: 200 mg 
IV Q3W
Efficacy Procedures
Tumor Imaging and 
Response Assessment
X
X
X
X
Screening imaging within 28 
days of first dose.  
On-study imaging every 9 
weeks (±7 days) from first 
dose, or as clinically indicated
MSI status testing of 
tumor tissue from CRPC 
participants 
X*
*CRPC participants who have 
an objective response
(confirmed or unconfirmed) to 
therapy will complete, if not 
previously done on an archival 
or newly obtained tumor 
sample.  Testing need only be 
completed once.
Subsequent anti-
neoplastic therapy status
X
X
X
X
 
 
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Trial Period:
Screening 
Phase
Treatment Phase  (21-day Treatment 
Cycles)
End of 
Treatment 
(EOT) / 
Discon-
tinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety Follow-
up
Imaging 
Follow-
up
Survival 
Follow-up
Treatment Days per 
Cycle:
1
3
8
1
1
1
At time of 
treatment 
discon.
30 days post 
last dose study 
medication
Every 12 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
± 3
± 3
± 3
+7
+7
± 7
± 7
Procedure windows may vary 
Survival Status
X
After investigator determined 
PD or start of new anticancer 
treatment. In addition, upon 
Sponsor request, participants 
may be contacted for survival 
status at any time during the 
course of the study.
Clinical 
Procedures/Assessments
Full physical examination
X
X
X
Directed Physical 
Examination
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
VS: heart rate, respiratory rate, 
blood pressure, temperature
12-lead ECG
X
Perform additional test as 
clinically indicated. 
ECOG Performance 
Status
X
X
X
X
X
X
X
 
 
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Trial Period:
Screening 
Phase
Treatment Phase  (21-day Treatment 
Cycles)
End of 
Treatment 
(EOT) / 
Discon-
tinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety Follow-
up
Imaging 
Follow-
up
Survival 
Follow-up
Treatment Days per 
Cycle:
1
3
8
1
1
1
At time of 
treatment 
discon.
30 days post 
last dose study 
medication
Every 12 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
± 3
± 3
± 3
+7
+7
± 7
± 7
Procedure windows may vary 
Laboratory Procedures/Assessments – Analysis by Local Lab
Serum β-Human 
Chorionic Gonadotropin 
or Urine Pregnancy Test
(β-hCG; Women of
childbearing potential 
(WOCBP) only)
X
• Additional urine/serum 
testing may be performed if 
clinically warranted, and/or as 
defined by local regulations.
• If a urine pregnancy test 
cannot be confirmed as 
negative, a serum pregnancy 
test is required. 
• Obtain urine pregnancy test 
within 72 hours prior to first 
dose.
Serum Follicle 
Stimulating Hormone 
(FSH) - (WOCBP only)
X
If necessary, to check 
menopausal status
HIV, Hepatitis B and C 
Screen (per site SOP)]
X
Acceptable to be based on 
history unless testing is 
required by local regulation.
Urinalysis
X*
X
X
X
X
*If screening assessment has 
been performed within 72 
hours prior to initiation of 
dosing, it does not need to be 
repeated on Cycle 1 Day 1.
Perform up to 72 hours before
Day 1 dosing; 
 
 
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Trial Period:
Screening 
Phase
Treatment Phase  (21-day Treatment 
Cycles)
End of 
Treatment 
(EOT) / 
Discon-
tinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety Follow-
up
Imaging 
Follow-
up
Survival 
Follow-up
Treatment Days per 
Cycle:
1
3
8
1
1
1
At time of 
treatment 
discon.
30 days post 
last dose study 
medication
Every 12 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
± 3
± 3
± 3
+7
+7
± 7
± 7
Procedure windows may vary 
Hematology including 
absolute neutrophil 
count (ANC)
X
X
X
X
X
X
X
X
X
Note: visit windows for this 
assessment vary as follows:

As a safety lab, hematology 
(including ANC) will be 
collected on Day 1 of every 
cycle pre-dose as follows:

On days when navarixin 
PK samples are
collected, pre-dose 
ANC should be 
collected within 2 hours 
prior to dosing.

On days when navarixin 
PK is not collected, pre-
dose ANC can be 
collected within 24 
hours prior to dosing.

In addition, for 
pharmacodynamics 
assessment, another sample 
will be collected between 6-
12 hours after dosing on 
Days 1, 3, and 8 of Cycle 1, 
and Day 1 of Cycle 2.
PT/INR and aPTT
X
Participants on anticoagulant 
therapy should be monitored
throughout the trial.
 
 
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Trial Period:
Screening 
Phase
Treatment Phase  (21-day Treatment 
Cycles)
End of 
Treatment 
(EOT) / 
Discon-
tinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety Follow-
up
Imaging 
Follow-
up
Survival 
Follow-up
Treatment Days per 
Cycle:
1
3
8
1
1
1
At time of 
treatment 
discon.
30 days post 
last dose study 
medication
Every 12 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
± 3
± 3
± 3
+7
+7
± 7
± 7
Procedure windows may vary 
Comprehensive 
Chemistry Panel
X
X
X
X
X
X
X
Note: visit windows for this 
assessment vary as follows (to 
be collected at same time as
hematology samples):

Chemistry panel will be 
collected on Day 1 of every 
cycle pre-dose as follows:

On days when navarixin 
PK samples are 
collected, pre-dose 
sample should be 
collected within 2 hours 
prior to dosing.

On days when navarixin 
PK is not collected, pre-
dose sample can be 
collected within 24 
hours prior to dosing.
 
 
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Trial Period:
Screening 
Phase
Treatment Phase  (21-day Treatment 
Cycles)
End of 
Treatment 
(EOT) / 
Discon-
tinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety Follow-
up
Imaging 
Follow-
up
Survival 
Follow-up
Treatment Days per 
Cycle:
1
3
8
1
1
1
At time of 
treatment 
discon.
30 days post 
last dose study 
medication
Every 12 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
± 3
± 3
± 3
+7
+7
± 7
± 7
Procedure windows may vary 
Thyroid Function (T3, or 
FT3, T4 or FT4, and 
TSH)
X
X
X
X
To be performed every other 
cycle (1, 3, 5, 7 etc.)
Note: visit windows for this 
assessment vary as follows (to 
be collected at same time as 
hematology samples):

Thyroid testing will be 
collected on Day 1 of every 
cycle pre-dose as follows:
On days when navarixin 
PK samples are collected, 
pre-dose sample should 
be collected within 2 
hours prior to dosing.
On days when navarixin 
PK is not collected, pre-
dose sample can be 
collected within 24 hours 
prior to dosing
Prostate-Specific Antigen 
(PSA)
X
X
X
Screening PSA within 28 days 
of date of allocation.  
In the first year, on-study PSA 
every 9 weeks (±7 days) from 
date of allocation.
After 1 year, in participants 
remaining on-study, PSA every 
12 weeks (±7 days)
 
 
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Trial Period:
Screening 
Phase
Treatment Phase  (21-day Treatment 
Cycles)
End of 
Treatment 
(EOT) / 
Discon-
tinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety Follow-
up
Imaging 
Follow-
up
Survival 
Follow-up
Treatment Days per 
Cycle:
1
3
8
1
1
1
At time of 
treatment 
discon.
30 days post 
last dose study 
medication
Every 12 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
± 3
± 3
± 3
+7
+7
± 7
± 7
Procedure windows may vary 
AE/SAE review
X
X
Pharmacokinetics/Pharmacodynamics/Future Biomedical Research/Biomarkers – Analysis 
by Central Lab
Blood for Genetic 
Analysis
X
Collect pre-dose. 
Peripheral Blood 
Mononuclear Cell
X
X
X
X
X
Collect pre-dose (up to 24
hours before dosing) on Day 1 
of Cycles 1-4, 6, and 8, and 
every 4 Cycles thereafter.
Blood for Immune 
Profiling
(immunophenotyping)
X
X
X
X
X
Collect pre-dose (up to 24
hours before dosing) on Day 1 
of each Cycle for Cycles 1-4, 6 
and 8, and every 4 Cycles 
thereafter.
Serum for 
Pembrolizumab 
Pharmacokinetics
X
X
X
Pre-dose (trough) PK samples 
will be collected within 24 
hours before infusion at Cycles 
1, 2, 4, 6, and 8 and every 4 
cycles thereafter
 
 
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Trial Period:
Screening 
Phase
Treatment Phase  (21-day Treatment 
Cycles)
End of 
Treatment 
(EOT) / 
Discon-
tinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety Follow-
up
Imaging 
Follow-
up
Survival 
Follow-up
Treatment Days per 
Cycle:
1
3
8
1
1
1
At time of 
treatment 
discon.
30 days post 
last dose study 
medication
Every 12 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
± 3
± 3
± 3
+7
+7
± 7
± 7
Procedure windows may vary 
Plasma for navarixin 
Pharmacokinetics
X
X
X
X
X
X
X
X
Note: All pre-dose navarixin 
PK samples must be collected 
within 10 minutes prior to 
dosing.
Cycle 1:
Day 1: Pre-dose (0), 1, 2, 4, 
and 6 h, and 1 sample between 
8 -12 h
Day 3: Pre-dose, 1 sample 
between 6 – 12 h
Day 8: Pre-dose, 1 sample 
between 6 -  12 h
Cycle 2:
Day 1: Pre-dose (0), 1, 2, 4, 
and 6 h, and  1 sample between 
8 -12 h
Cycle 3:
Day 1: Pre-dose (trough)
Cycle 4:
Day 1: Pre-dose (trough)
After Cycle 4:
Same scheme as for 
pembrolizumab PK
 
 
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Trial Period:
Screening 
Phase
Treatment Phase  (21-day Treatment 
Cycles)
End of 
Treatment 
(EOT) / 
Discon-
tinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety Follow-
up
Imaging 
Follow-
up
Survival 
Follow-up
Treatment Days per 
Cycle:
1
3
8
1
1
1
At time of 
treatment 
discon.
30 days post 
last dose study 
medication
Every 12 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
± 3
± 3
± 3
+7
+7
± 7
± 7
Procedure windows may vary 
Anti-Pembrolizumab 
Antibodies
X
X
X
Anti-pembrolizumab antibody 
samples will be collected 
within 24 hours before infusion 
at Cycles 1, 2, 4, 6, 8 and every 
4 cycles thereafter
Blood for Serum Protein 
Analysis
X
X
X
X
Blood for serum protein 
analysis should be collected 
pre-dose on Day 1 of each 
Cycle.
Blood for RNA Analysis
X
X
X
X
Blood for RNA Analyses 
should be collected pre-dose on 
Day 1 of Cycle 1, Cycle 2, and 
Cycle 5, and at treatment 
discontinuation 
Tumor Tissue Collection
Archival and/or Newly 
Obtained Tissue 
Collection
X
X*
*optional on-treatment biopsy. 
To be performed after 
scheduled blood draws.
 
 
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3. Introduction
Navarixin (MK-7123, formerly SCH 527123), is an orally bioavailable, potent, and specific 
small molecule antagonist of the CXC G protein-coupled receptor CXCR1/2, with 
substantially higher affinity for CXCR2 than CXCR1. It is in development for once daily 
dosing for use in combination therapy with pembrolizumab for the treatment of advanced 
solid tumors. Three tumor types will be evaluated in this study: PD-(L)1 refractory non-small 
cell lung cancer (NSCLC), castration resistant prostate cancer, and microsatellite stable 
(MSS) colorectal cancer (CRC).
Study Rationale 
3.1
Myeloid-derived suppressor cells (MDSCs) are an adverse cancer-wide prognostic 
population of immune infiltrating cells [Gentles, A. J., et al 2015]. MDSCs contribute to 
tumor immune evasion through a variety of mechanisms that suppress local T-cell activation 
and viability [Gentles, A. J., et al 2015] [Condamine T, Ramachandran I, Youn JI, 
Gabrilovich DI. 2015]. MDSCs can also influence tumor progression by promoting tumor 
metastases, angiogenesis and tumor cell invasion [Condamine T, Ramachandran I, Youn JI, 
Gabrilovich DI. 2015]. The relief of myeloid suppression of T cell function could enhance 
pembrolizumab responses and this mechanism is being actively interrogated to increase the 
number of durable clinical responses.
The CXC G protein-coupled receptor, CXCR2, is highly expressed on human MDSCs and 
plays a role in the homing of MDSCs in the tumor microenvironment (TME). The CXCR2 
receptor is highly expressed across tumor types and has been shown to significantly correlate 
with poor survival [Steele CW, Karim SA, Leach JDG, Bailey P, Upstill-Goddard R 2016] 
[Saintigny, P., et al 2013] [Li, L., et al 2015]; internal Moffitt/TCGA database analysis). 
For example, in late stage prostate cancer, CXCR2-MDSCs have been suggested to play a 
critical role in prostate tumor progression [Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S 
2016]. Hormonal therapy and chemotherapy have been shown to enrich for CXCR2 positive 
cells in prostate cancer patients. In addition to promoting tumor resistance by enhancing the 
immunosuppressive TME through MDSC recruitment, reports have shown that the ELRCXC 
chemokine-CXCR1/2 axis can promote angiogenic responses and activate epithelial-
mesenchymal transition (EMT) differentiation programs which are associated with its role in 
metastasis and stemness [David JM, Dominguez C, Hamilton DH, Palena C. 2016] 
[Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J 2012].  
This Phase 2 POC trial will investigate 3 tumor types that express CXCR2, and have a low 
objective response rate to PD-(L)1 inhibitor monotherapy: NSCLC (PD-(L)1 refractory), 
castration resistant prostate, and MSS colorectal cancers, in order to test the  hypothesis that 
navarixin added to pembrolizumab may improve treatment outcomes.
Background
3.2
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on navarixin and the MK-3475 IB/approved labeling for detailed background 
information on pembrolizumab. 
 
 
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Pharmaceutical and Therapeutic Background
3.2.1
Navarixin is a CXCR2 antagonist.
Navarixin Pharmaceutical and Therapeutic Background
3.2.1.1
The ELRCXC chemokine-CXCR1/2 axis mediates pleiotropic effects that impact 
tumorigenesis: 1) promotion of tumor resistance by enhancing the immunosuppressive tumor 
microenvironment (TME) by recruitment of neutrophils/myeloid-derived suppressor cells 
(MDSCs), 2) promotion of angiogenic responses, and 3) activation of epithelial-mesenchyme 
transition (EMT), which is associated with metastasis and stemness [David JM, Dominguez 
C, Hamilton DH, Palena C. 2016] [Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim 
J 2012] [Condamine T, Ramachandran I, Youn JI, Gabrilovich DI. 2015].
CXCR2 antagonists function to inhibit the translocation of granulocytes (including 
neutrophils) out of the marrow and into circulation (and, inhibit translocation of MDSCs into 
tumors) [Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E 2014].  As expected, the 
class of CXCR2 antagonists demonstrates a mechanism-based decrease in circulating 
neutrophils.  Therefore, the neutrophil count serves as an easily monitorable functional 
biomarker assay.  Navarixin clinical trials have demonstrated a dose-dependent decrease in 
neutrophils, suggesting the molecule is sufficient to test the hypothesis: CXCR2 antagonism, 
in combination with pembrolizumab, improves outcomes for cancer patients relative to 
pembrolizumab alone.
MDSCs are present and active in a number of different tumor types [David JM, Dominguez 
C, Hamilton DH, Palena C. 2016] [Kumar V, Patel S, Tcyganov E, Gabrilovich DI. 2016].  
Likewise, CXCR2 is expressed in a diverse set of tumors.  Recent data suggest that CXCR2 
antagonism might reverse tumor immune suppression caused by MDSCs [Highfill SL, Cui Y, 
Giles AJ, Smith JP, Zhang H, Morse E 2014] [Theivanthiran B, DeVito NC 2017].  In 
addition, antagonism of CXCR2 has been shown to inhibit tumor metastasis and neo-
angiogenesis in preclinical models. CXCR2 inhibition in combination with immunotherapy 
shows enhanced anti-tumor activity (anti-PD-1/anti-CTLA-4) in a preclinical prostate model
[Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P 2017]. CXCR2 inhibition enhances 
T cell entry, suppresses metastases, and confers sensitivity to anti-PD-1 treatment in KPC
PDAC model. In addition, disruption of CXCR2-mediated MDSC tumor trafficking enhances 
anti-PD-1 efficacy in a syngeneic RMS tumor models. Moreover, data indicates that 
navarixin treatment can enhance the anti-tumor activity of PD-1 blockade in a B16-F10 
syngeneic tumor model that shows modest activity to anti-PD-1 as a monotherapy (complete 
responses observed in the combination arm). 
No studies with navarixin have been initiated in oncology indications. However, it was 
previously developed by Schering for non-oncology indications (chronic obstructive 
pulmonary disease [COPD], asthma, psoriasis).  As a result of this development, over 900 
subjects were treated with navarixin in clinical trials. Several Phase II studies were conducted 
in COPD, asthma, and psoriasis. No impact of treatment was observed in the psoriasis study. 
Two small asthma studies showed trends to clinically significant results.
 
 
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The largest Phase II trial was a proof of concept (POC) study in patients with moderate to 
severe COPD in which navarixin 50 mg was compared with placebo. Navarixin treatment led 
to statistically significant improvement in forced expiratory volume (FEV) in patients with 
COPD who were current smokers. Treatment discontinuations for Grade 2 neutropenia were 
observed.  No increases in infections or fevers were observed in treated patients versus the 
placebo group.  Navarixin development was discontinued due to the modest and restricted 
(current smokers) observed benefit.
Multiple Phase I studies in healthy volunteers confirm that navarixin induces a dose 
dependent peripheral reduction in neutrophils; 24% and 48% median ANC decrease for 30 
and 100 mg respectively.  Neutrophil migration from the marrow is inhibited, and no marrow 
hypo-cellularity was observed.  The neutrophil reduction is rapidly reversible on dosing 
cessation, and peripheral neutrophils return to baseline values in 48-96 hours without 
cytotoxic or myelosuppressive effects on the bone marrow.  
Several CXCR2 antagonists are under development.  AstraZeneca has reported AZD5069 
Phase 1 results in combination with durvalumab [Steele CW, Karim SA, Leach JDG, Bailey 
P, Upstill-Goddard R 2016].  The combination is reported to be well-tolerated, and the 
AZD5069 combination with durvalumab does not appear to enhance toxicities observed from 
either AZD5069 or durvalumab monotherapies.
Navarixin development will focus on combinations with immune checkpoint inhibitors 
(pembrolizumab).  The removal of the immune suppression induced by navarixin, combined 
with immune checkpoint abrogation, is hypothesized to improve cancer therapy outcomes 
relative to either treatment alone.  The mechanistic, dose-dependent, rapidly reversible, 
decrease in peripheral neutrophils induced by navarixin (and all CXCR2 antagonists) will 
serve as a readily monitorable pharmacodynamic marker in this trial.
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic Background
3.2.1.2
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a number of 
indications. For more details on specific indications, refer to the pembrolizumab IB.
Benefit/Risk Assessment
3.3
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
 
 
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4. Objectives/Hypotheses and Endpoints
Male/female participants of at least 18 years of age with selected advanced/metastatic solid 
tumors will be enrolled in this study.
Objective
Endpoint
Primary

Objective: To evaluate the objective 
response rate (ORR) as assessed by the 
investigator based on Response 
Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1) following 
administration of navarixin in 
combination with pembrolizumab.

Objective response is a confirmed 
complete response (CR) or partial 
response (PR).

Objective: To determine the safety and 
tolerability of navarixin in combination 
with pembrolizumab.

Dose-limiting toxicity (DLT)

Adverse event (AE)

Discontinuing study treatment due to 
an AE.  
Secondary

Objective: To evaluate objective 
response rate (ORR) as assessed by 
investigator based on iRECIST 
(modified RECIST 1.1) [Seymour, L., 
et al 2017], progression-free survival 
(PFS) as assessed by investigator based 
on RECIST 1.1 and iRECIST, and 
overall survival (OS) following 
administration of navarixin in 
combination with pembrolizumab

Objective response is a confirmed CR 
or PR.

PFS is time from the first dose of study 
medication to the first documented 
disease progression or death due to any 
cause, whichever occurs first.

OS is time from the first dose of study 
medication to death due to any cause.

Objective: To evaluate the 
pharmacodynamics as measured by 
absolute neutrophil counts (ANC) 
following administration of navarixin 
in combination with pembrolizumab. 

ANC in 109/L

Objective: To evaluate the 
pharmacokinetics (PK) of navarixin
when administered in combination with 
pembrolizumab

PK parameters including area under the 
curve (AUC) in ng·hr/mL, maximum 
concentration (Cmax) in ng/mL, trough 
concentration (Ctrough) in ng/mL
 
 
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Objective
Endpoint
Tertiary/Exploratory

Objective: To evaluate the 
development of circulating anti-
pembrolizumab antibodies, as 
appropriate, following administration 
of  navarixin in combination with 
pembrolizumab

Anti- pembrolizumab antibody level

Objective: To evaluate the relationship 
between navarixin PK and ANC

ANC; navarixin PK parameters 
including AUC, Cmax, and Ctrough

Objective: 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 of navarixin in 
combination with pembrolizumab.

Germline genetic variation, genetic 
(deoxyribonucleic [DNA]) mutations 
from tumor, tumor and blood 
ribonucleic acid (RNA) variation, 
proteomics and immunohistochemistry 
(IHC), and other blood-derived 
biomarkers
5. Study Design 
Overall Design 
5.1
This is a stratified, parallel, 2-arm (2-dose), randomized, uncontrolled multicenter study of 
navarixin in combination with pembrolizumab in participants with selected 
advanced/metastatic solid tumors. The study will use a 2-stage adaptive design based on pre-
specified criteria. There is no untreated/placebo comparator arm.
Participants with PD-(L)1 refractory NSCLC, CRPC, or MSS CRC will be randomized into 
one of two dose arms.  In dose Arm A, participants will be treated with 30 mg orally QD 
navarixin.  In dose Arm B, participants will be treated with 100 mg orally QD navarixin.  
Participants in both Arms A and B will be treated concomitantly with pembrolizumab 200 
mg IV Q3W.
Per the interim safety analysis, if no more than 3 participants in the first 10 evaluable
participants have experienced DLTs during the first cycle in an arm, this arm may be 
expanded by enrolling an additional 20 participants to complete Stage 1. However, during 
Stage 1, if at any time >3 DLTs are observed within the first 10 evaluable participants, 
enrollment into an arm will be discontinued. 
In addition, the following stopping rule is included for excessive toxicity occurring outside 
the current defined DLT window. If 4 or more of the first 10 evaluable participants have a 
DLT per current protocol definition (either within the first cycle DLT observation window or 
outside this window) after they have all finished the first cycle observation, enrollment into 
the arm may be discontinued unless totality of the data (eg, including efficacy) supports a 
favorable risk-benefit trade-off.
 
 
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Safety and tolerability will be continuously monitored throughout the study duration.  If the 
regimen is deemed intolerable, the arm may be discontinued even if stopping rule is not met.
The overall design is an adaptive 2-stage design.  In each arm, up to 30 participants will be 
enrolled in the first stage, and up to 30 participants in the second stage.  In the first stage, 30 
participants (with 10 per tumor type) will be enrolled in each arm (dose level). When all 
participants in a given arm with a given tumor type complete the first on-treatment scan at 9 
weeks or when clinically indicated (see Section 9.2.1.2), a futility analysis will be conducted 
to determine whether that tumor type and arm will progress to Stage 2. If a tumor type passes
the futility analysis (see Section 5.1.4) in Stage 1, at least 10 participants will be enrolled 
with that tumor type in the second stage.
Initial enrollment in each dose arm will be staggered.  The first 3 participants in dose Arm A 
or dose Arm B will be enrolled no more frequently than 1 participant per week, to allow for 
peripheral neutrophil assessment between participants.  Peripheral neutrophil assessment 
(ANC) will occur at baseline, Day 3, and Day 8 during the first cycle for all participants.  
Decreased ANC counts typically return to normal in 48-96 hours following dosing cessation. 
Standard support for oncology patients with low ANC will be considered as appropriate.  See 
dose reduction algorithm (Section 7.2.1) for more information.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Study SoA - Section 2. Details of each 
procedure are provided in Section 9 – Study Assessments and Procedures.
 
 
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Study Diagram
5.1.1
The study design is depicted in Figure 1.
Figure 1
Study Design
 
 
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Guidance for dose decision and expansion is depicted in Figure 2.
Figure 2
Guidance for Dose Decision and Expansion
Evaluation of Safety
5.1.2
In order to adequately evaluate the safety of the doses administered, all participants enrolled 
must meet the criteria for evaluability for Cycle 1.
Participants are considered nonevaluable for DLT evaluation if:

They are randomized but not treated.

They discontinue from the study prior to completing all the safety evaluations in 
Cycle 1 for reasons other than treatment-related adverse events.

They receive <75% of the total MK-3475 (or pembrolizumab) infusion and/or 
navarixin in Cycle 1 (eg, if the infusion had to be discontinued due to an infusion 
reaction) and they did not experience a DLT.
 
 
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Dose Limiting Toxicity
5.1.3
Formal DLT evaluation will be performed at the interim safety analysis, following 
completion of one cycle of treatment by 10 evaluable participants in each dose arm. DLT 
nonevaluable participants will not be replaced. For example, if one of the first 10 participants 
in an arm is nonevaluable for DLT, then the next DLT evaluable participant enrolled and 
treated in the arm will be included in the interim safety analysis. The DLT evaluation period 
will be for one cycle (Day 1 to Day 21.  Day 1 is considered the date a study drug was first 
administered and not the date of randomization if dosing did not occur on the date of 
randomization). During this time, supportive treatment with G-CSF will not be allowed.
An arm dose will be considered intolerable if >3 of 10 evaluable participants experience 
DLTs in Cycle 1. If the arm dose is not tolerated at 30 mg (and 100 mg), the arm may be 
discontinued and the protocol may be amended to include a lower navarixin dose. 
All toxicities will be graded based on investigator assessment (Appendix 4 “Assessment of 
Intensity”).  
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 treatment:
1) Grade 4 non-hematologic toxicity (not laboratory)
2) Grade 4 anemia of any duration
3) Grade 3 anemia lasting >7 days or requiring transfusion
4) Grade 4 hematologic toxicity (other than anemia) lasting ≥7 days, except 
thrombocytopenia
a) Grade 4 thrombocytopenia of any duration
b) Grade 3 thrombocytopenia associated with bleeding
5) Grade 3 non-hematologic toxicity (not laboratory) lasting >3 days despite optimal 
supportive care.
6) Any Grade 3 or Grade 4 non-hematologic laboratory value if:
•
Medical intervention is required to treat the participant, or
•
The abnormality leads to hospitalization, or
•
The abnormality persists for >72 hours. 
Exceptions:
•
Clinically non-significant, treatable, or reversible laboratory abnormalities 
including uric acid
 
 
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7) 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 
aminotransferase(s) (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
8) 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°) for more than one 
hour.
9) Inability to administer ≥75% of the planned navarixin dose due to drug-related 
tolerability.
10) Delay in starting Cycle 2 by >2 weeks due to toxicity.
Futility Analysis
5.1.4
An interim futility analysis for efficacy will be performed after the first 10 participants for 
each tumor type have at least 1 post-baseline scan assessment in each dose arm in Stage 1. If 
one or more responses (confirmed or unconfirmed) are observed for a tumor type in an arm
(i.e. ≥10% response rate), this tumor type may be expanded to enroll at least additional 10 
participants in Stage 2, for a maximum enrollment of 60 participants in this arm across 3 
tumor types. Otherwise, this tumor type may be stopped early for futility. 
If the decision is made to expand a tumor type in dose Arm A to Stage 2, this tumor type in 
dose Arm B may be expanded to Stage 2 as well, irrespective of the number of responses as 
long as it has passed the safety evaluation. While the decision rule is mainly based on 
confirmed and unconfirmed responses, the totality of data will also be taken into account.
Number of Participants
5.2
Greater than or equal to 120 participants will be randomized in order to achieve 120
evaluable participants as per Section 10. If no efficacy is noted in any tumor types the total 
number may be as low as 60.
Beginning and End of Study Definition
5.3
The overall study begins when the first participant signs the informed consent form (ICF).  
The overall study ends when the last participant completes the last study-related phone-call 
or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to be 
contacted by the investigator).  
 
 
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Clinical Criteria for Early Study Termination
5.3.1
Early study 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 participants
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 participant treatment can be made.
Scientific Rationale for Study Design 
5.4
This Phase 2 study is being conducted to evaluate the efficacy, safety, and tolerability of 
navarixin in selected solid tumors when administered in combination with pembrolizumab. 
Two different doses of navarixin (30 mg and 100 mg QD) will be evaluated in combination 
with the standard dose of pembrolizumab (200 mg Q3W). 
Rationale for Endpoints
5.4.1
Efficacy Endpoints
5.4.1.1
A primary objective for this trial is to evaluate the antitumor activity of navarixin in 
combination with pembrolizumab in participants with selected advanced or metastatic solid 
tumors. Tumor response (ORR) in participants with solid tumors will be assessed using 
RECIST 1.1 based on investigator assessment. Images will be collected for possible analysis 
by blinded, independent central review.
ORR will be used for decision making. A time to event endpoint (e.g., PFS, OS) would 
require a control group (preferably placebo controlled, blinded). Given that the participants in 
this study have refractory disease, and have disease that is not responsive to PD-1 
antagonists, ORR is considered evidence of efficacy, and has formed the basis for accelerated 
approval (for oncology agents) in the US.
Immunotherapeutic agents such as navarixin and pembrolizumab may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses. The response patterns 
seen with such an approach may extend beyond the typical time course of responses seen 
with typical cytotoxic agents, and can manifest a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions. Standard response assessment criteria 
may not provide a comprehensive response assessment of immunotherapeutic agents such as 
navarixin and pembrolizumab. Therefore, as a secondary objective, ORR will also be 
assessed by iRECIST. 
Additional secondary objectives include evaluation of PFS by RECIST 1.1 and iRECIST and 
OS of participants treated with navarixin in combination with pembrolizumab.
For additional details about assessing efficacy endpoints using RECIST 1.1 and iRECIST, 
see Appendix 7 in Section 12.
 
 
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Safety Endpoints
5.4.1.2
A primary objective of this trial is to characterize the safety and tolerability of navarixin in 
participants with advanced/ metastatic solid tumors when administered in combination with 
pembrolizumab.  The primary safety analysis will be based on participants who experience 
toxicities as defined by CTCAE Version 4.0.3 criteria. Safety will be assessed by quantifying 
the toxicities and grades of toxicities experienced by participants who have received 
navarixin in combination with pembrolizumab.
Safety parameters commonly used for evaluating investigational systemic anti-cancer 
treatments are included as safety endpoints for the study including, but not limited to, the 
incidence of, causality to, and outcome of AEs/SAEs; changes in vital signs and laboratory 
values. Adverse events will be assessed as defined by CTCAE, Version 4.0.3.
Pharmacokinetic Endpoints
5.4.1.3
A secondary objective of this study is to characterize the PK profile of navarixin and 
pembrolizumab following administration of navarixin in combination with pembrolizumab. 
The systemic concentrations of these agents will serve as the primary readout for the PK, and 
these data will be used to derive PK parameters for these agents when administered in 
combination. Furthermore, the results of these analyses will be used in conjunction with the 
PD, safety, and exploratory endpoint data to help assess future dosing strategies for 
navarixin.
Pharmacodynamic Endpoints
5.4.1.4
Existing data from prior clinical studies for respiratory therapies indicate that navarixin
causes a dose-dependent decrease in neutrophils. While this may limit dosing, its target-
mediated nature (CXCR2 mediates neutrophil trafficking) and existence of available clinical 
data also make it a suitable biomarker for target modulation due to navarixin activity. In 
addition, reports from competitors (AZD5069) [Steele CW, Karim SA, Leach JDG, Bailey P, 
Upstill-Goddard R 2016] support the mechanism-based observed ANC reduction observed 
after navarixin blockade of CXCR2 signaling. Absolute neutrophil counts (ANC) will be 
used to evaluate target engagement/modulation and its relationship to pharmacokinetics 
endpoints. In addition, ANC levels will be closely monitored during the course of the trial to 
identify if there are any instances of neutropenia that may affect participant safety.
 
 
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Planned Exploratory Biomarker Research
5.4.1.5
Cancer immunotherapies represent an important and novel class of anti-tumor agents.  
However, the mechanism of action of these 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 identify novel 
predictive/pharmacodynamic biomarkers and generate information that will better guide 
therapies with immuno-oncology drugs. To identify novel biomarkers, biospecimens (ie, 
blood components, tumor material) will be collected to support analyses of cellular 
components (eg, protein, DNA, RNA, metabolites) and other circulating molecules.  
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, single-nucleotic polymorphism [SNP] analyses, 
whole exome sequencing, whole genome sequencing)
This research will evaluate whether genetic variation within a clinical study 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.  Finally, microsatellite 
instability (MSI) may be evaluated as this is an important biomarker for some cancers (ie, 
colorectal cancer).
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 (ie, mutations, methylation 
status, microsatellite instability).  Key molecular changes of interest to immune-oncology 
drug development include 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.  Microsatellite instability may also be 
evaluated as this is an important biomarker for some cancers (ie, colorectal cancer).
Tumor/blood RNA analysis: Both genome-wide and targeted messenger RNA (mRNA) 
expression profiling and sequencing in tumor tissue and/or blood may be performed to define 
gene signatures that correlate to clinical response to treatment with pembrolizumab in 
combination with navarixin or other immunotherapies. Pembrolizumab induces a response in 
tumors that likely reflects an inflamed/immune phenotype. Specific immune-related gene sets 
(ie, those capturing IFN-γ transcriptional pathways) may be evaluated and new signatures 
may be identified. In addition, expression levels of the targeted receptor CXCR2 and 
correlation to response may also be investigated. MicroRNA profiling may also be pursued.
 
 
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Immunohistochemistry (IHC) in tumor biopsies: Mechanistic studies carried out in 
preclinical models of melanoma (B16-F10) and colon carcinoma (CT26) showed a 
significant reduction in granulocytic MDSC infiltration in tumors after navarixin treatment. 
IHC in tumor biopsies will be used to assess changes in myeloid and lymphoid cell content in 
tumor biopsies as a result of navarixin treatment. In addition, PD-L1 status by IHC will also 
be determined.
Participants will be required to provide an archival tumor tissue sample and/or a fresh biopsy 
of tumor before treatment for these biomarker analyses. Participants will also be asked to 
agree to a biopsy of tumor after initiation of study treatment and to provide the acquired 
tissue for these biomarker analyses.
Other blood/serum derived biomarkers: In addition to expression within the tumor tissue, 
tumor-derived proteins can be shed from tumor and released into the blood.  In the case of 
proteins, enzyme-linked immunosorbent assays can measure such proteins in serum and 
plasma and correlate this expression with response to pembrolizumab plus navarixin
combination therapy. Previous clinical trials (P05575) and published competitor data have 
reported concentration changes in the CXCR2 ligands GRO-α and IL-8, and in the 
neutrophil-associated enzyme MMP-9, after pathway blockade. In addition, changes in serum
IL-8 levels have been shown to reflect and predict response to anti-PD-1 treatment in 
melanoma and NSCLC .Changes in IL-8, GRO-a, and MMP-9 concentrations as a result of 
combination therapy will be evaluated by enzyme-linked immunoassay.
Planned Genetic Analysis
5.4.1.5.1
Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a sample will be 
collected for DNA analysis from consenting participants.
DNA samples will be used for research related to the study treatment(s), the disease under 
study and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to the disease under study, related diseases and study drug(s). Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be
conducted if it is hypothesized that this may help further understand the clinical data. The 
samples may be analyzed as part of a multi-study assessment of genetic factors involved in
the response to understand study disease or related conditions.
Future Biomedical Research
5.4.1.6
The Sponsor will conduct Future Biomedical Research on specimens for which consent was 
provided during this study.  This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
 
 
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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 study) and will only be conducted on specimens from 
appropriately consented participants. 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 
participants receive the correct dose of the correct drug/vaccine at the correct time.  The 
details of this Future Biomedical Research sub-study are presented in Appendix 2  –
Collection and Management of Specimens for Future Biomedical Research.
Justification for Dose 
5.5
Starting Dose for This Study
5.5.1
An exposure response (ER) analysis from previous clinical experience was conducted to 
establish the relationship between navarixin AUC and % reduction in absolute neutrophil 
count (ANC – functional biomarker of navarixin activity) from baseline. The ER analysis 
revealed a dose-dependent decrease in neutrophils. The 30 mg and 100 mg doses were 
chosen as there was a clear differentiation in % ANC reduction between the 2 doses and the 
% ANC reduction corresponding to exposures at the 100 mg dose were at the plateau of the 
ER relationship. The low dose (30 mg PO QD) induced a moderate decrease in circulating 
neutrophils, while the higher dose (100 mg PO QD) induced a greater reduction. 
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab across all indications and regardless of tumor type. As 
outlined below, this dose is justified by: 

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W)

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 
mg/kg Q3W vs. 10 mg/kg Q3W (KN001 B2, KN001 D, KN002, KN010, and KN021), and 3
studies compared 10 mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2 and KN006). 
All of these studies demonstrated flat dose- and exposure-response relationships across the 
doses studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg 
(or 200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
 
 
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Subsequently, flat dose-/exposure-response relationships were also observed in other tumor 
types including head and neck cancer, bladder cancer, gastric cancer, and classical Hodgkin 
Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor type. 
These findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
Maximum Dose/Exposure for This Study
5.5.2
The maximum pre-planned dose of navarixin that will be used in this study is 100 mg QD.
Evidence from the percent ANC reduction versus dose data suggests that the 100 mg dose is 
near the plateau of the exposure response relationship.  Higher doses may be considered if
supported by clinical PK/PD and efficacy data.
Rationale for Dose Interval and Study Design
5.5.3
Navarixin
Multiple doses of up to 50 mg navarixin, administered for up to 12 weeks in participants with 
moderate-to-severe COPD, were found to be safe and well-tolerated.  Multiple doses of 
navarixin, 30 mg QD, administered for up to 10 days in participants with mild asthma and up 
to 4 weeks in participants with severe asthma, were found to be safe and well tolerated. The 
effect of navarixin on ANCs was similar following both the single-dose and multiple doses.  
At 24 hours post dosing, the median percent ANC reduction for 30 and 100 mg navarixin 
(orally) was 24% and 48%, respectively. There were no other significant changes in clinical 
laboratory parameters, vital signs, and electrocardiograms.  
Navarixin, 30 mg QD, significantly reduced ANCs and sputum neutrophils in participants 
with COPD, along with early signs of clinical improvement. Navarixin, 30 mg QD, resulted 
in a significant reduction in ANCs and sputum neutrophils in participants with severe asthma 
and demonstrated an improvement in asthma control, as well as a reduction in the rate of 
mild asthma exacerbations. Single dose administration of 100 mg navarixin in healthy 
volunteers was safe and well tolerated in healthy participants. Multiple doses of 100 mg 
navarixin administered QD for up to 14 days in healthy participants was safe and well 
 
 
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tolerated. There was a significant but reversible decline in ANCs after both single and 
multiple doses of 100 mg.
While preliminary signals of clinical benefit were observed in navarixin-treated asthma and 
COPD patients, this efficacy was not sufficient to warrant continued development in these 
indications.
Following multiple daily oral administration of 10, 30, 50, and 100 mg navarixin, plasma 
concentration steady state was achieved by Day 11; navarixin minimum observed plasma 
concentration (Cmin) values were similar on Days 11 through 14. There was little to no 
accumulation of navarixin observed in plasma on Day 14 with mean accumulation ratio (R) 
values ranging from 1.05 to 1.21. 
Pembrolizumab
The planned dose and dosing interval of pembrolizumab for this study is 200 mg every 3 
weeks (Q3W). Based on the totality of data generated in the Keytruda development program, 
200 mg Q3W is the appropriate dose of pembrolizumab for adults across all indications and 
regardless of tumor types. 
No pembrolizumab dose modifications are planned for this study.
6. Study Population
Male and female participants of at least 18 years of age, with selected advanced/metastatic
solid tumors (NSCLC [PD-(L)1 refractory], CRPC, and MSS CRC) will be enrolled in this 
study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
6.1
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics – All Participants
1. Have one of the following histologically- or cytologically-confirmed 
advanced/metastatic (diagnosis of Stage IV [AJCC version 8 or current version as 
applicable]) solid tumors (NSCLC, CRPC, or MSS CRC) by pathology report and 
have received, or been intolerant to, or have been ineligible for all treatment known 
to confer clinical benefit.
2. Have Stage III or Stage IV disease that is not surgically resectable.
3. Have measureable disease by RECIST 1.1 criteria as assessed by the local site 
investigator/radiology. Lesions situated in a previously irradiated area are 
considered measureable if progression has been demonstrated in such lesions.
4. Have supplied tumor tissue from either a newly obtained biopsy or an archival 
specimen from a site not previously irradiated for biomarker analysis.
 
 
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Non-small cell lung cancer (NSCLC) Participants Only
5. Have a histologically or cytologically confirmed diagnosis of Stage IV metastatic 
NSCLC.
6. Stage IV metastatic NSCLC tumors that are PD-(L)1 positive (TPS ≥50%), do not 
harbor EGFR-sensitizing mutations and ALK translocations that are amenable to 
treatment with respective tyrosine kinase inhibitor therapy, and who have received 
prior treatment with a PD-(L)1 antagonist
7. Must have progressed on treatment with an anti-PD-(L)1 monoclonal antibody 
(mAb) administered either as monotherapy, or in combination with other 
checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by 
meeting all of the following criteria:
a.
Has received at least 2 doses of an approved anti-PD-(L)1 mAb.
b. Has demonstrated disease progression after anti-PD-(L)1 as defined by 
RECIST 1.1 The initial evidence of disease progression (PD) is to be 
confirmed by a second assessment no less than 4 weeks from the date of the 
first documentation of PD in the absence of rapid clinical progression.(This 
determination will have been made by the investigator. Once PD is 
confirmed, the initial date of PD documentation will be considered the date 
of disease progression).
c.
Progressive disease has been documented within 12 weeks from the last 
dose of anti-PD-(L)1 mAb.
Castration Resistant Prostate Cancer (CRPC) Participants Only
8. Have histologically- or cytologically-confirmed (if acceptable according to local
health authority regulations) adenocarcinoma of the prostate. Components of small 
cell prostate cancer are permitted.  Diagnosis must be stated in a pathology report 
and confirmed by the investigator.
9. Have prostate cancer progression on the most recent treatment, as determined
by the investigator, by means of one of the following:
a. PSA progression using local laboratory values as defined by a minimum of 2 
rising PSA levels with an interval of ≥1 week between each assessment where
the PSA value at screening should be ≥2 ng/mL
b. Radiographic disease progression in soft tissue based on RECIST 1.1 criteria 
with or without PSA progression.
c. Radiographic disease progression in bone defined as the appearance of 2 or 
more new bone lesions on bone scan with or without PSA progression.
Note: Radiographs must be collected and transmitted to the central imaging
vendor at study entry.
 
 
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10. Must have progressed on at least one second generation anti-androgen therapy (e.g., 
enzalutamide, abiraterone) according to PCWG3 guidelines.
11. Have ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM).
a.
If the participant is currently being treated with luteinizing hormone-releasing 
hormone agonists or antagonists (participants who have not undergone an 
orchiectomy), this therapy must have been initiated at least 4 weeks prior to 
first dose of trial treatment and treatment must be continued throughout the 
study.
Microsatellite Stable Colorectal Cancer (MSS-CRC) Participants Only
12. Have a histologically proven locally advanced unresectable or metastatic (Stage IV) 
CRC.
13. Have locally confirmed microsatellite stable (MSS) CRC; participants with 
microsatellite instability-high (MSI-H) or microsatellite unstable CRC are not 
eligible.
14. Have been previously treated with standard therapies, which must include 
fluoropyrimidine, oxaliplatin, and irinotecan.
a.
Participants who have withdrawn from standard treatment due to unacceptable 
toxicity warranting discontinuation of that treatment and precluding 
retreatment with the same agent before progression of disease will also be 
eligible.
b. Regimens given with adjuvant intent will be counted as treatment for 
metastatic disease if the participant’s disease had progressed within 6 months 
following treatment.
Demographics – All Participants
15. Men and women who are ≥18 years of age.
16. Have an ECOG performance status of 0 or 1.
Male participants:
17. A male participant must agree to use contraception as detailed in Appendix 3 of this 
protocol during the treatment period and for at least 120 days after the last dose of 
study treatment and refrain from donating sperm during this period.
 
 
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Female participants:
18. A female participant is eligible to participate if she is not pregnant (see Appendix 
3), not breastfeeding, and at least one of the following conditions applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR 
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3
during the treatment period and for at least 120 days after the last dose of study 
treatment.
Informed Consent
19. The participant (or legally acceptable representative if applicable) provides written 
informed consent/assent for the study.  The participant may also provide 
consent/assent for Future Biomedical Research.  However the participant may 
participate in the main study without participating in Future Biomedical Research.
Laboratory Values – All Participants
20. Demonstrate adequate organ function as defined by the following table (Table 1).
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
>1,500/mcL
Platelets a
>100,000/mcL
Hemoglobin a
≥9 g/dL or ≥5.6 mmol/L 
Renal
Serum creatinine or
creatinine clearance (CrCl) (measured or
calculated) b or
Glomerular Filtration Rate (GFR) in place of 
CrCl
≤1.5 X upper limit of normal (ULN) or
≥60 mL/min for participant with creatinine levels 
>1.5 X ULN
Hepatic
Total bilirubin 
≤1.5 X ULN or 
Direct bilirubin ≤1.5 X ULN for participants with 
total bilirubin levels >1.5 X ULN; if there is no 
institutional ULN, then direct bilirubin must be 
<40% of total bilirubin to be eligible. Note: In no 
case can the total bilirubin exceed 3 X ULN.
Aspartate aminotransferase (AST) and Alanine 
aminotransferase (ALT)
≤2.5 X ULN or ≤5 X ULN for participants with 
liver metastases
Coagulation
International Normalized Ratio (INR) or
Prothrombin Time (PT)
≤1.5 X ULN unless participant is receiving 
anticoagulant therapy
Activated Partial Thromboplastin Time (aPTT) 
or Partial Thromboplastin Time (PTT)
≤1.5 X ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
 
 
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System
Laboratory Value
a Criteria must be met without packed red blood cell (pRBC) transfusion within last 2 weeks.  Participants can 
be on stable dose of erythropoietin (≥ approximately 3 months).
b Creatinine clearance (CrCl) should be calculated per institutional standard. If no local guideline is available, 
creatinine clearance should be calculated using the Cockcroft-Gault Method: CrCl = ([140-age] * weight [kg] * 
[0.85 for females only]) / (72 * serum creatinine)
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.
Exclusion Criteria 
6.2
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has a known additional malignancy that is progressing or has required active 
treatment within the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
2. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, ie, without evidence of progression for at least 4 weeks by repeat imaging 
(note that the repeat imaging should be performed during study screening), clinically 
stable and without requirement of steroid treatment for at least 14 days prior to first 
dose of study treatment.
3. Has had a severe hypersensitivity reaction to treatment with any monoclonal antibody
or components of the study drug(s).
4. Has an active autoimmune disease that has required systemic treatment in the past 2 
years (ie, 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 nonsystemic steroids is permitted. In 
addition to active autoimmune disease, participants who have previously been 
permanently discontinued from PD-(L)1 therapy due to immune related side effects 
are not eligible for the study.
5. Has an active infection requiring systemic therapy.
6. Has symptomatic ascites or pleural effusion. A participant who is clinically stable 
following treatment for these conditions (including therapeutic thoracocentesis or 
paracentesis) is eligible.
7. Has interstitial lung disease that required oral or intravenous glucocorticoids to assist 
with management.
 
 
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8. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
9. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 
5 years.
Note: Participants who have had a stem cell transplant >5 years ago are eligible as 
long as there are no symptoms of graft-versus-host disease (GVHD).
10. Has a known history of human immunodeficiency virus (HIV) infection. 
Note: No HIV testing is required unless mandated by local health authority.
11. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
12. Has a history or current evidence of a gastrointestinal (GI) condition (eg, 
inflammatory bowel disease, Crohn’s disease, ulcerative colitis) or impaired liver 
function or diseases that in the opinion of the Investigator may significantly alter the 
absorption or metabolism of oral medications; any condition, therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the 
participant’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 participant to participate, in the opinion of the treating 
Investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
14. Is pregnant or expecting to conceive or father children within the projected duration 
of the study.
15. Has undergone major surgery and has not recovered adequately from any toxicity 
and/or complications from the intervention prior to starting study therapy.
16. A WOCBP who has a positive urine pregnancy test within 72 hours before the first 
dose of study treatment (see Appendix 3).  If the urine test cannot be confirmed as 
negative, a serum pregnancy test is required.  In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.
Prior/Concomitant Therapy
17. Participants with CRPC or MSS CRC who have received prior therapy with an anti-
PD-1, anti-PD-(L)1, or anti PD L2 agent. 
18. Have been treated with an agent directed to another stimulatory or co-inhibitory T-
cell receptor (eg, CTLA-4, OX 40, CD137).
 
 
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19. Has received prior systemic anti-cancer therapy including investigational agents or 
has used an investigational device within 28 days prior to the first dose of study 
treatment. Note: Participants must have recovered from all AEs due to previous 
therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy or alopecia 
may be eligible. Participants receiving ongoing replacement hormone therapy for 
endocrine immune-related adverse events (eg, thyroid replacement therapy) will not 
be excluded from participation in this study.
20. Has received prior radiotherapy (not to target lesions) within 2 weeks of start of study 
treatment.  Participants must have recovered from all radiation-related toxicities, not 
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
21. Is expected to require any other form of antineoplastic therapy while on study.
22. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
in excess of replacement doses (prednisone ≤10 mg/day is acceptable), or on any 
other form of immunosuppressive medication.
Note: The use of physiologic replacement doses of corticosteroids may be 
approved after consultation with the Sponsor Medical Monitor or designee.
23. Has received a live-virus vaccine within 30 days prior to first dose of study 
medication. Vaccines that do not contain live virus are permitted.
Prior/Concurrent Clinical Study Experience
24. Had been previously treated with a CXCR2 inhibitor (eg, AZD5069, reparixin, 
danirixin, LY3041658 Ab, HuMax-IL8, etc.)
Lifestyle Restrictions
6.3
There are no lifestyle restrictions.
Screen Failures
6.4
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any adverse events or serious adverse events (SAE) meeting reporting 
requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
6.5
A participant who discontinues from study treatment or withdraws from the study will not be 
replaced.
 
 
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7. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment.  Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
Treatments Administered
7.1
The study treatments to be used in this study are outlined below in Table 2 Study 
Treatment(s).
Table 2
Study Treatment(s)
Study 
Treatment Name:
Navarixin 
(MK-7123)
Pembrolizumab 
(MK-3475)
Dosage Formulation:
Oral dry filled 
capsule
Solution for 
Infusion
Unit Dose Strength(s):
Two potencies:
10-mg and 50-mg 
capsules  
100 mg/vial
Dosage Level(s):
30 mg QD
100 mg QD
200 mg Q3W
Route of 
Administration:
Oral
IV infusion
Sourcing:
Provided centrally 
by the Sponsor. 
Provided 
centrally by the 
Sponsor. 
All supplies indicated in Table 2 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The study site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to Section 9.1.8 for details regarding administration of the study treatment.
 
 
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Dose Modification  
7.2
Navarixin Dose Modification
7.2.1
For Grade 4 ANC, or febrile neutropenia (Grade 3 or 4 ANC), navarixin will be held for 1 
week to allow the ANC to recover.  ANC will be measured for recovery at 1 week (local 
draw is permissible).  If ANC has recovered to Grade 1 or better, the participant will be 
restarted at a lower dose of navarixin (ie, from 100 mg to 50 mg or from 30 mg to 20 mg), 
depending on the dose arm.  If the participant has not recovered, he/she will return to the 
clinic in one week for a second ANC draw.  If ANC has recovered to Grade 1 or better, the 
participant will be restarted at a lower dose of navarixin (ie, from 100 mg to 50 mg or from 
30 mg to 20 mg), depending on the arm.  If not recovered, he/she will discontinue navarixin, 
but remain on pembrolizumab treatment.  There will only be one dose reduction per arm.  If 
the participant experiences Grade 4 ANC or febrile neutropenia while already dosed reduced, 
the participant will discontinue navarixin treatment (Table 3).
For immune related AEs, see Section 7.2.2 for pembrolizumab dosing instructions.  If 
pembrolizumab dosing is held, navarixin dosing should also be held. If pembrolizumab 
dosing is resumed, navarixin dosing may be restarted at a lower dose.  If navarixin has 
already been dose reduced, then navarixin should be discontinued Table 3 and Section 7.2.2).
For DLTs (Section 5.1.3) not encompassed under irAEs (Section 7.2.2), both navarixin and 
pembrolizumab will be held for 1 week (an additional extension period for recovery of the 
toxicity may be allowed, following consultation with the Sponsor and the investigator). Then, 
if toxicity has recovered to Grade 1 or better (or participant’s baseline value), participant will 
be restarted on the standard dose of pembrolizumab and a lower dose of navarixin (ie, from 
100 mg to 50 mg or from 30 mg to 20 mg), depending on the dose arm.  There will only be 
one navarixin dose reduction per arm.  Therefore, if the participant experiences the DLT 
while already dosed reduced, the participant will discontinue navarixin, but may restart the 
standard dose of pembrolizumab following recovery (Table 3).
 
 
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Table 3
Navarixin/Study Drug Dose Modifications
Toxicities
Navarixin Dosing
Action
Grade 4 ANC
Hold navarixin for 1 
week for ANC to 
recover.

If ANC recovered to Grade 1 or 
better, participant will be restarted 
at lower dose of navarixin (ie, from 
100 mg to 50 mg or from 30 mg to 
20 mg), depending on the arm.

If ANC has not recovered, 
participant will receive a second 
ANC test after an additional 1 week

If ANC recovered to Grade 1 
or better, participant will be 
restarted at lower dose of 
navarixin (ie, from 100 mg 
to 50 mg or from 30 mg to 
20 mg), depending on the 
arm.

If ANC has not recovered, 
participant will discontinue 
navarixin treatment, but will 
continue to receive 
pembrolizumab treatment.
Febrile 
neutropenia 
(Grade 3 or 4 
ANC)
Hold navarixin for 1 
week for ANC to 
recover.

If ANC recovered to Grade 1 or 
better, participant will be restarted 
at lower dose of navarixin (ie, from 
100 mg to 50 mg or from 30 mg to 
20 mg), depending on the arm.

If ANC has not recovered, 
participant will receive a second 
ANC test after an additional 1 week

If ANC recovered to Grade 1 
or better, participant will be 
restarted at lower dose of 
navarixin (ie, from 100 mg 
to 50 mg or from 30 mg to 
20 mg), depending on the 
arm.

If ANC has not recovered, 
participant will discontinue 
navarixin treatment, but will 
continue to receive 
pembrolizumab treatment.
 
 
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Toxicities
Navarixin Dosing
Action
Grade 4 ANC or 
febrile 
neutropenia while 
navarixin already 
dosed reduced
There will be only 1 
dose reduction per arm.

Participant will discontinue 
navarixin.
Study Medication 
Dosing
Immune related 
AEs (irAEs) which 
require 
pembrolizumab
dose modification 
(See Section 7.2.2)
Follow Section 7.2.2 
for pembrolizumab 
dosing instructions.
Hold navarixin while 
pembrolizumab is held
to allow irAE to 
recover.

Hold/discontinue pembrolizumab 
dosing according to instructions in 
Section 7.2.2

Hold navarixin while 
pembrolizumab is held.

If pembrolizumab is restarted, 
restart navarixin at lower dose of 
navarixin (ie, from 100 mg to 50 mg 
or from 30 mg to 20 mg), depending 
on the arm.

If navarixin has already been dose 
reduced, discontinue navarixin.
DLTs not 
described above 
(see Section 5.1.3)
Hold navarixin for 1 
week* for DLT to 
recover.
Hold pembrolizumab 
while navarixin is held.
*An additional 
extension period for 
recovery of the toxicity 
may be allowed, 
following consultation 
with the Sponsor and 
the Investigator.

If toxicity has recovered to Grade 1 
or better (or participant’s baseline 
value), participant will be restarted 
at lower dose of navarixin (ie, from 
100 mg to 50 mg or from 30 mg to 
20 mg), depending on the arm.  If 
navarixin has already been dose 
reduced, discontinue navarixin. 
Pembrolizumab will be restarted at 
normal dose.

If toxicity has not recovered, 
participant will discontinue study
treatment (discontinue both 
pembrolizumab and navarixin).
 
 
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Pembrolizumab Dose Modification
7.2.2
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 4.
 
 
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related AEs
Toxicity grade or 
conditions (CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids (initial 
dose of 1-2mg/kg 
prednisone or 
equivalent) followed by 
taper

Monitor participants for signs and 
symptoms of pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or recurrent 
grade 2
Permanently discontinue
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids (initial 
dose of 1-2mg/kg 
prednisone or 
equivalent) followed by 
taper

Monitor participants for signs and 
symptoms of enterocolitis (i.e. 
diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) 
and of bowel perforation (i.e. 
peritoneal signs and ileus).

Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing 
endoscopy to rule out colitis. 

Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids.  If sufficient 
oral fluid intake is not feasible, fluid 
and electrolytes should be substituted 
via IV infusion.
Grade 4
Permanently discontinue
 
 
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General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related AEs
Toxicity grade or 
conditions (CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
AST / ALT elevation or 
increased bilirubin
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose of 0.5- 1mg/kg 
prednisone or 
equivalent) followed by 
taper

Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently discontinue

Administer 
corticosteroids (initial 
dose of 1-2mg/kg 
prednisone or 
equivalent) followed by 
taper
Type 1 diabetes mellitus 
(T1DM) or 
Hyperglycemia
Newly onset T1DM or 
Grade 3 or 4 
hyperglycemia associated 
with evidence of -cell 
failure
Withhold

Initiate insulin 
replacement therapy for 
participants with T1DM 

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 

Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4 
Withhold or permanently 
discontinue1
 
 
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General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related AEs
Toxicity grade or 
conditions (CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective 
beta-blockers (e.g. 
propranolol) or 
thionamides as 
appropriate 

Monitor for signs and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withhold or 
permanently discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid 
replacement hormones 
(e.g. levothyroxine or 
liothyroinine) per 
standard of care

Monitor for signs and symptoms of 
thyroid disorders. 
Nephritis and renal 
dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(prednisone 1-2mg/kg or 
equivalent) followed by 
taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently discontinue
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer 
corticosteroids

Ensure adequate evaluation to 
confirm etiology and/or exclude other 
causes
Grade 3 or 4
Permanently discontinue
 
 
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General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related AEs
Toxicity grade or 
conditions (CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
All other immune-related 
AEs
Intolerable/ persistent 
Grade 2
Withhold

Based on type and 
severity of AE 
administer 
corticosteroids 

Ensure adequate evaluation to 
confirm etiology and/or exclude other 
causes
Grade 3
Withhold or discontinue 
based on the type of 
event.  Events that 
require discontinuation 
include and not limited 
to:  Gullain-Barre 
Syndrome, encephalitis
Grade 4 or recurrent Grade 
3 
Permanently discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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Method of Treatment Assignment 
7.3
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system.  There are 2 study treatment arms.  Participants will be assigned 
randomly in a 1:1 ratio to dose Arm A and dose Arm B, respectively.
Stratification
7.3.1
Treatment allocation/randomization will be stratified according to the following factors:
Tumor type (NSCLC [PD-(L)1 refractory], CRPC, and MSS CRC)
Blinding 
7.4
This is an open-label study; therefore, the Sponsor, investigator and participant will know the 
treatment administered.
Preparation/Handling/Storage/Accountability
7.5
Dose Preparation
7.5.1
Details on preparation and administration of navarixin (and pembrolizumab) are provided in 
the appropriate Pharmacy/Procedures Manual
Handling, Storage and Accountability
7.5.2
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study 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.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
 
 
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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 study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
7.6
Interruptions from the protocol specified treatment plan for >12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
Concomitant Therapy
7.7
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed. 
If there is a clinical indication for any medication or vaccination specifically prohibited, 
discontinuation from study 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 participant’s 
primary physician. However, the decision to continue the participant on study treatment
requires mutual agreement of the investigator, the Sponsor, and the participant. 
Participants are prohibited from receiving the following concomitant therapies and
vaccinations during the screening and treatment periods of the study:

Immunotherapy not specified in this protocol

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol

Investigational agents not specified in this protocol

Radiation therapy (radiotherapy for symptom management is allowed)

Live vaccines within 28 days before the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chickenpox, yellow fever, rabies, BCG, and 
typhoid vaccines. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. Intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines, and are not allowed.

Glucocorticoids other than to modulate symptoms from an immune-mediated AE. 
Chronic systemic replacement doses of steroids and non-systemic steroids including 
inhaled steroids, topical steroids, intra-nasal steroids, intra-articular, and ophthalmic 
steroids are allowed.
There are no prohibited therapies after the Post-Treatment Safety Follow-Up visit.
Rescue Medications and Supportive Care
7.7.1
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 7.2, (Table 4).  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
 
 
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not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance.  Refer to (Table 4) in Section 
7.2.1 for guidelines regarding navarixin dose modification and supportive care. Refer to 
Section 7.2.2 for pembrolizumab dose modification.
Supportive Care Guidelines for Pembrolizumab
Pneumonitis:
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids. Administer
additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of prolonged
steroid administration.
Diarrhea/Colitis:
Participants should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and bowel 
perforation (such as peritoneal signs and ileus).
o
All participants who experience diarrhea/colitis should be advised to drink liberal
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea,
consider GI consultation and endoscopy to confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis that persists >3 days, administer oral corticosteroids.
o
For Grade 3 or 4 diarrhea/colitis that persists >1 week, treat with intravenous
steroids followed by high dose oral steroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and
continued over no less than 4 weeks.
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA):
o
For T1DM or Grade 3-4 hyperglycemia

Insulin replacement therapy is recommended for Type 1 diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.
Evaluate patients with serum glucose and a metabolic panel, urine ketones,
glycosylated hemoglobin, and C-peptide.
 
 
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Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks.
Replacement of appropriate hormones may be required as the steroid dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.
Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in
thyroid function (at the start of treatment, periodically during treatment, and as indicated
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine
or liothyronine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism

Treat with an initial dose of IV corticosteroid followed by oral corticosteroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started
and continued over no less than 4 weeks. Replacement of appropriate
hormones may be required as the steroid dose is tapered.
Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to
baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and
continued over no less than 4 weeks
Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and
continued over no less than 4 weeks.
Myocarditis:
o
For Grade 1 or 2 events, withhold. Based on severity of AE administer 
corticosteroids. Ensure adequate evaluation to confirm etiology and/or exclude other 
causes.
 
 
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o
For Grade 3 and 4 events, permanently discontinue. Based on severity of AE 
administer corticosteroids. Ensure adequate evaluation to confirm etiology and/or 
exclude other causes.
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.
Table 5 shows treatment guidelines for participants who experience an infusion reaction
associated with administration of pembrolizumab (MK-3475).
Table 5
Pembrolizumab Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
None
Grade 2
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hours
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 
participant is deemed medically 
stable in the opinion of the 
investigator.
If symptoms resolve within one hour 
of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (e.g., from 
100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms 
resolve and the participant should be 
premedicated for the next scheduled 
dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration.
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab (MK-
3475) with:
Diphenhydramine 50 mg 
orally (or equivalent dose 
of antihistamine).
Acetaminophen 500-1000 
mg orally (or equivalent 
dose of antipyretic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates)
Stop Infusion.
Additional appropriate medical 
therapy may include but is not limited 
to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
No subsequent dosing
Grade 4:
Life-threatening; pressor or 
ventilatory support 
indicated
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
Hospitalization may be indicated.
Participant is permanently 
discontinued from further trial 
treatment administration.
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration.
 
 
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Treatment After the End of the Study 
7.8
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
7.9
This study is open-label; therefore, the participant, the study site personnel, the Sponsor 
and/or designee are not blinded. Study treatment (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
8. Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
8.1
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 2 - Schedule of Activities 
and Section 9.11.3 – Post Study.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the study plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9 – Discontinuation and Withdrawal.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
The participant interrupts study treatment administration for more than 12 consecutive 
weeks, unless approved with written documentation from the Sponsor.
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.
o
The participant has a confirmed positive serum or urine pregnancy test (depending on 
local regulation).
Withdrawal from the Study
8.2
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
 
 
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Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 9.1.9 – Withdrawal/Discontinuation.The procedures to be performed 
should a participant repeatedly fail to return for scheduled visits and/or if the study site is 
unable to contact the participant are outlined in section 8.3.
Lost to Follow Up
8.3
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
●
The site must attempt to contact the participant and reschedule the missed visit.  If the 
participant is contacted, the participant 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 
participant at each missed visit (eg, phone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
●
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant.  The missing data for the participant will be managed 
via the pre-specified statistical data handling and analysis guidelines.
9. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
The Investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff.  Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were
performed within the time frame defined in the SoA.
 
 
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●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent be obtained 
from the participant.  In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required is outlined in the Procedure 
Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
9.1
Informed Consent
9.1.1
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical study or Future Biomedical Research. If there are changes to the participant’s status 
during the study (eg, health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate consent is in place. 
General Informed Consent
9.1.1.1
Consent must be documented by the participant’s dated signature or by the participant’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 participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use.  
The participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the study.  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 participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature.
Specifics about a study and the study 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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Consent and Collection of Specimens for Future Biomedical Research
9.1.1.2
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the participant, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-study.  A copy of 
the informed consent will be given to the participant.
Inclusion/Exclusion Criteria
9.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
Participant Identification Card
9.1.3
All participants will be given a Participant Identification Card identifying them as 
participants in a research study. The card will contain study site contact information 
(including direct telephone numbers) to be utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a Participant Identification 
Card immediately after the participant provides written informed consent. At the time of 
treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
9.1.4
General Medical History
9.1.4.1
A medical history will be obtained by the investigator or qualified designee.
Medical history will include all active conditions, drug allergies, significant medical 
procedures and any condition diagnosed within the prior 10 years that are considered to be 
clinically significant by the investigator. Any cancer other than the cancer under study will 
be recorded as medical history even if diagnosed greater than 10 years prior to enrollment.  
Details regarding the cancer under study will be recorded separately and not listed as medical
history.
Oncologic Disease Details
9.1.4.2
The investigator or qualified designee will obtain historic and current details of the 
participant’s cancer under study.  This information will include, but is not limited to, date of 
diagnosis, stage, histology, locations of primary lesions and location of metastases if 
applicable.
 
 
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Prior and Concomitant Medications Review
9.1.5
Prior Medications
9.1.5.1
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before the first dose of study medication.  Any medications taken to treat a 
cancer other than the cancer under study will be recorded as a prior medication even if taken 
greater than 28 days before the first dose of study medication.  All treatments for the cancer 
under study will be recorded separately and not listed as a prior medication.
Prior Oncologic Treatment
9.1.5.2
The investigator or qualified designee will review and record all treatments for the cancer 
under study including systemic and local treatment, vaccinations, radiation, and surgeries.  
Additional information collected on these treatments will include, but is not limited to, 
reason for discontinuation, best response, and date of progression after each treatment as 
applicable.
Concomitant Medications
9.1.5.3
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 9.3.
Any new anti-cancer therapy started after the participant’s discontinuation from the treatment 
period will be recorded separately.  Additional information collected on this treatment will 
include, but is not limited to, best response and date of progression.
Assignment of Screening Number
9.1.6
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.  Each participant 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 9.11.1.  
Assignment of Treatment/Randomization Number
9.1.7
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
 
 
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A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
9.1.8
Study treatment should start on the day of treatment allocation/randomization or as close as 
possible to the date on which the participant is allocated/assigned.
Timing of Dose Administration
9.1.8.1
Navarixin may be administered at any time in relation to food intake.  Navarixin should be 
taken at approximately the same time each day.
Discontinuation and Withdrawal
9.1.9
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal).  Any 
adverse events which are present at the time of withdrawal should be followed in accordance 
with the safety requirements outlined in Section 9.3..
Withdrawal From Future Biomedical Research
9.1.9.1
Participants may withdraw their consent for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main study.  If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com).  
Subsequently, the participant'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 participant 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 
study data and results.  No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
9.1.10
This is an open label study; there is no blinding for this study.
Domiciling
9.1.11
Participants will not be domiciled.
 
 
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Calibration of Equipment
9.1.12
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Efficacy Assessments 
9.2
Tumor Imaging and Assessment of Disease
9.2.1
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual (SIM).  Tumor imaging is strongly preferred to be acquired 
by computed tomography (CT).  For the abdomen and pelvis, contrast-enhanced magnetic 
resonance imaging (MRI) may be used when CT with iodinated contrast is contraindicated, 
or when mandated by local practice.  MRI is the strongly preferred modality for imaging the 
brain.  The same imaging technique regarding modality, ideally the same scanner, and the 
use of contrast should be used in a participant throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the 
accuracy of the assessment of response or progression based on imaging.  Note: for the 
purposes of assessing tumor imaging, the term “Investigator” refers to the local investigator 
at the site and/or the radiological reviewer located at the site or at an offsite facility.
All scheduled images for all study participants from the sites will be submitted to the central 
imaging vendor.  In addition, images (including via 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 based on Investigator assessment, should 
also be submitted to the central imaging vendor. 
Initial Tumor Imaging
9.2.1.1
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
randomization.  The site study team must review screening images to confirm the participant 
has measurable disease per RECIST 1.1.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to 
the date of randomization and can be assessed by the central imaging vendor.
If brain imaging is performed to document the stability of existing metastases, MRI should 
be used if possible.  If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative.
 
 
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Tumor Imaging During the Study
9.2.1.2
The first on-study imaging assessment should be performed at 9 weeks (±7 days) from the 
date of randomization. Subsequent tumor imaging should be performed every 9 weeks (±7 
days) 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 is identified by the Investigator or the start of new 
anticancer treatment, withdrawal of consent, or death, whichever occurs first. All 
supplemental imaging must be submitted to the central imaging vendor. 
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.  
Note:  Response does not typically need to be verified in real time by the central imaging 
vendor.
Per iRECIST (Section 9.2.1.5), disease progression should be confirmed by the site 4 to 8 
weeks after first radiologic evidence of PD in clinically stable participants. Participants who 
have unconfirmed disease progression may continue on treatment at the discretion of the 
Investigator until progression is confirmed by the site, provided they have met the conditions 
detailed in Section 9.2.1.5. Participants who receive confirmatory imaging do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point, if clinically stable. Participants who 
have confirmed disease progression by iRECIST, as assessed by the site, will discontinue 
study treatment. Exceptions are detailed in Section 9.2.1.5
End of Treatment and Follow-up Tumor Imaging
9.2.1.3
For participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study treatment due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment every 12 weeks (±7 days) until the start 
of a new anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, 
or the end of the study, whichever occurs first.
RECIST 1.1 Assessment of Disease
9.2.1.4
RECIST 1.1 (assessed by investigator) will be used as the primary measure for assessment of 
tumor response, date of disease progression, and as a basis for all protocol guidelines related 
to disease status (eg, discontinuation of study treatment).
 
 
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iRECIST Assessment of Disease
9.2.1.5
The iRECIST method is based on RECIST 1.1, but adapted to account for the unique tumor 
response seen with immunotherapeutic drugs. iRECIST will be used by the Investigator to 
assess tumor response and progression, and make treatment decisions. When clinically stable, 
participants should not be discontinued until progression is confirmed by the Investigator, 
working with local radiology, according to the rules outlined in Appendix 7. This allowance 
to continue treatment despite initial radiologic PD takes into account the observation that 
some participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of 
disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the Investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment.  Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule.  If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has iRECIST confirmed radiographic progression (iCPD) as defined in 
Appendix 7, study treatment should be discontinued; however, if the participant is achieving 
a clinically meaningful benefit, an exception to continue study treatment may be considered 
following consultation with the Sponsor.  In this case, if study treatment is continued, tumor 
imaging should continue to be performed following the intervals as outlined in Section 2 and 
submitted to the central imaging vendor. 
A description of the adaptations and iRECIST process is provided in Appendix 7, with 
additional details in the iRECIST publication  [Seymour, L., et al 2017].
Guidance for imaging and treatment after first radiologic evidence of progressive disease is 
shown in Table 6 and for clinically stable participants in Figure 3.
 
 
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Table 6
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 that 
has been verified 
by BICR]
Repeat imaging 
at 4 to 8 weeks to 
confirm PD.
May continue study 
treatment at the 
investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST.
Repeat imaging 
at 4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
investigator 
assessment
No additional 
imaging required.
Discontinue 
treatment (exception 
is possible upon 
consultation with 
Sponsor).
No additional 
imaging required.
Not applicable
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per investigator 
assessment
Repeat imaging 
at 4 to 8 weeks to 
confirm PD.  
May occur at next 
regularly 
scheduled 
imaging visit.
Continue study 
treatment at the 
investigator’s 
discretion.
Repeat imaging 
at 4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue treatment
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
treatment at the 
investigator’s 
discretion.
Continue 
regularly 
scheduled 
imaging
assessments.
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion.  Next tumor 
imaging should occur 
according to the regular 
imaging schedule.
 
 
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Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigators
iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; PD=progressive 
disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1
Prostate-Specific Antigen
9.2.2
The initial Prostate-Specific Antigen (PSA) biomarker assessment at screening must be
performed within 28 days prior to the date of allocation.
In the first year (through Week 54), on study PSA biomarker assessments must be performed
every 9 weeks (63 days ±7 days) from the date of allocation. After one year, participants who
remain on-treatment will have PSA performed every 12 weeks (84 days ±7 days).
MSI Status in CPRC Patients
9.2.3
MSI status will be tested in participants with CRPC who demonstrate an objective response
(either confirmed or unconfirmed) to therapy.  
MSI status can be evaluated using the archival or newly obtained tumor tissue collected at 
screening.
Adverse Events (AE), Serious Adverse Events (SAE) and Other Reportable Safety 
9.3
Events 
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Appendix 4.
 
 
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Progression of the cancer under study is not considered an adverse event as described in 
Section 9.3.5 – Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs, and Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
Adverse events will not be collected for participants during the pre-screening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention.  If the participant requires a blood draw, fresh 
tumor biopsy etc., the participant is first required to provide consent to the main study and 
AEs will be captured according to guidelines for standard AE reporting.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
9.3.1
Safety Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
●
All AEs from the time of treatment allocation/randomization through 30 days 
following cessation of study treatment must be reported by the investigator. 
●
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following 
cessation of study treatment if the participant initiates new anticancer therapy, 
whichever is earlier must be reported by the investigator. 
●
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 
30 days following cessation of study treatment if the participant initiates new 
anticancer therapy must be reported by the investigator. 
●
Additionally, any SAE brought to the attention of an investigator at any time outside 
of the time period specified above must be reported immediately to the Sponsor if the 
event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 7.
 
 
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Table 7
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE)
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
 
 
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Method of Detecting AE, SAE and Other Reportable Safety Events
9.3.2
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
9.3.3
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE
9.3.4
●
Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 
●
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
●
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
9.3.5
or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 9.3.1.  
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 participants in the study.  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.
 
 
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Pregnancy and Exposure During Breastfeeding
9.3.6
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee), including the pregnancy of a male participant's 
female partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events).  If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Events of Clinical Interest (ECI)
9.3.7
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this study include: 
1. an overdose of Sponsor's product, as defined in Section 9.4 – Treatment of Overdose, 
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 study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
Treatment of Overdose
9.4
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for navarixin ≥200 mg and for pembrolizumab ≥1000 mg (ie, ≥5 times the indicated 
dose). No specific information is available on the treatment of overdose of navarixin and 
pembrolizumab. In the event of overdose, navarixin and pembrolizumab should be 
discontinued and the participant should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated.
Safety 
9.5
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the study (from pre-study to post-study visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in Section 9.
Planned time points for all safety assessments are provided in the SoA.
 
 
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Physical Examinations
9.5.1
Full Physical Exam
9.5.1.1
The Investigator or qualified designee will perform a complete physical exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 2. After the first 
dose of study treatment, new clinically significant abnormal findings should be recorded as 
AEs.
Directed Physical Exam
9.5.1.1.1
For cycles that do not require a full physical exam as defined in Section 2, the Investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to the 
administration of the study treatment. New clinically significant abnormal findings should be 
recorded as AEs.
Vital Signs
9.5.2
The investigator or qualified designee will take vital signs at screening, prior to each 
pembrolizumab infusion, and during the follow-up period as specified in the Schedule of 
Activities. 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, and pulse. 
Electrocardiograms
9.5.3
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the Schedule of Activities in Section 2.0. Clinically significant 
abnormal findings at Screening should be recorded as medical history. Additional ECG(s)
should be performed when clinically necessary.
Clinical Safety Laboratory Assessments
9.5.4
Refer to Appendix 5 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Appendix 5, must be 
conducted in accordance with the laboratory manual and the SoA.
 
 
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●
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
●
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 
Pharmacokinetics
9.6
To evaluate the immunogenicity and exposure of pembrolizumab and exposure of navarixin
in this indication, sample collections for analysis of anti-drug antibodies (ADA; anti-
pembrolizumab antibodies) and PK are currently planned as shown in the Schedule of 
Activities. Blood samples for PK and ADA collected may be stored only at this time. Further 
analysis may be performed if required. If ongoing PK and/or ADA sampling is deemed to be 
unnecessary by the Sponsor, it may be reduced or discontinued. 
Blood Collection for Plasma Navarixin 
9.6.1
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual. 
Note: All pre-dose navarixin PK samples must be collected within 10 minutes prior to 
dosing.
Cycle 1
9.6.1.1
Samples will be collected on:
Day 1: Pre-dose (0), 1, 2, 4, and 6 hours, and 1 sample between 8 - 12 hours
Day 3: Pre-dose, and 1 sample between 6 - 12 hours
Day 8: Pre-dose, and 1 sample between 6 - 12 hours
Cycles 2 to 4
9.6.1.2
Samples will be collected on: 
Cycle 2:
Day 1: Pre-dose (0), 1, 2, 4, and 6 hours, and 1 sample between 8 - 12 hours
Cycle 3:  
Pre-dose (trough)
Cycle 4:
Pre-dose (trough)
 
 
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After Cycle 4
9.6.1.3
Samples will collected according to the same schedule as for pembrolizumab PK samples.
Blood Collection for Pembrolizumab
9.6.2
Samples will be collected at pre-dose (trough) within 24 hours before infusion at Cycles 1, 2, 
4, 6, and 8 and every 4 cycles thereafter.
Pharmacodynamics
9.7
Venous blood samples for safety and pharmacodynamics will be collected for measurement 
of neutrophil counts and neutrophil-to-lymphocyte ratios at pre-specified time points as 
outlined in the Schedule of Activities. Sample collection, storage, and shipment instructions 
for blood samples will be provided in the Procedures Manual.
As a safety lab, hematology (including ANC) will be collected on Day 1 of every cycle pre-
dose as follows:

On days when navarixin PK samples are collected, pre-dose ANC should be 
collected within 2 hours prior to dosing.

On days when navarixin PK is not collected, pre-dose ANC can be collected 
within 24 hours prior to dosing.
In addition, for pharmacodynamic assessment, another sample will be collected between 6-12 
hours after dosing on Days 1, 3, and 8 of Cycle 1, and Day 1 of Cycle 2.
Biomarkers
9.8
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA. Sample 
collection, storage, and shipment instructions for the exploratory biomarker specimens will 
be provided in the laboratory manual.

Blood for Genetic Analysis

Peripheral Blood Mononuclear Cell

Blood for Immune Profiling (immunophenotyping)

Blood for Serum Protein Analysis

Blood for RNA Analyses

Archival and/or Newly Obtained Tissue Collection
The Planned Genetic Analysis sample should be drawn for planned analysis of the 
association between genetic variants in DNA and drug response. This sample will not be 
collected at the site if there is either a local law or regulation prohibiting collection, or if the 
IRB/IEC does not approve the collection of the sample for these purposes. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the 
participant signs the Future Biomedical Research consent. If the planned genetic analysis is 
 
 
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not approved, but Future Biomedical Research is approved and consent is given, this sample 
will be collected for the purpose of Future Biomedical Research.
Future Biomedical Research Sample Collection 
9.9
If the participant signs the Future Biomedical Research consent, the following specimens will 
be obtained as part of Future Biomedical Research:

DNA for future research

Leftover cells from Peripheral Blood Mononuclear Cell

Leftover serum from Serum Protein Analysis

Leftover RNA from Blood for RNA Analyses

Leftover main study tumor
Health Economics
9.10
Patient reported outcomes will not be assessed in this study.
Visit Requirements
9.11
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
9.11.1
Approximately 28 days prior to treatment randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 6.1.  
Screening procedures may be repeated after consultation with the Sponsor.
Written consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant 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 
study treatment except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of study 
treatment. An exception is hepatitis testing which may be done up to 28 days prior to 
the first dose of study treatment if required.

Evaluation of ECOG is to be performed within 7 days prior to date of randomization.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of study treatment. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study site laboratory).

Archival tumor sample collection is not required to be obtained within 28 days prior 
to the first dose of study treatment. Newly obtained tumor tissue may be obtained 
within 90 days of treatment initiation.
 
 
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Participants 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. Participants who are rescreened will retain their original 
screening number.
Treatment Period
9.11.2
Visit requirements are outlined in the SoA (Section 2). Specific procedure-related details are 
provided in Section 9.1.
Post-Study
9.11.3
Safety Follow-up Visit
9.11.3.1
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anticancer treatment, whichever 
comes first. If a participant discontinues from the treatment period approximately 30 days or 
later after the last dose of study treatment a separate Safety Follow-up visit does not need to 
be completed. The End of Treatment/Discontinuation visit should be completed only and 
include any assessments required at the Safety Follow-up visit but not the discontinuation 
visit.
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Participants 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 anticancer therapy, whichever occurs first. Serious AEs that occur within 
90 days of the end of treatment or before initiation of a new anticancer treatment should also 
be followed and recorded. 
Disease Status Follow-up
9.11.3.2
Participants who discontinue study treatment for a reason other than disease progression per 
RECIST 1.1/iRECIST will move into the Follow-Up Phase and should be assessed as 
outlined in the SoA (Section 2) to monitor disease status. The Sponsor may request survival 
status to be assessed at additional time points during the course of the study (not to exceed 
approximately 12 weeks). Every effort should be made to collect information regarding 
disease status until the start of new anti-cancer therapy, disease progression, death, end of 
study. Information regarding post-study anticancer treatment will be collected if new 
treatment is initiated.
Survival Follow-up
9.11.3.3
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first.
 
 
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Survival Status
9.11.4
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an interim 
and/or final analysis. Upon Sponsor notification, all participants who do not/will not have a 
scheduled visit or study contact during the sponsor defined time period will be contacted for 
their survival status (excluding participants that have a previously recorded death event in the 
collection tool).
10. Statistical Analysis Plan 
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other nonconfirmatory 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 nonconfirmatory analyses made 
after the protocol has been finalized, but prior to final database lock, 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
10.1
This section contains a brief summary of the statistical analyses for this trial. Full details are 
in the Statistical Analysis Plan, Section 10.2 through Section 10.12.
Study Design Overview
Phase 2 trial of navarixin in combination with 
pembrolizumab in participants with selected 
advanced/metastatic solid tumors.
Analysis Populations
Efficacy (Primary and Secondary): Full Analysis Set (FAS)
Safety (Primary): All Participants as Treated (ASaT) and 
DLT evaluable population
PK and PD (Secondary): Per-Protocol (PP)
Primary Endpoint(s)
Efficacy: objective response is a confirmed complete 
response (CR) or partial response (PR).
Safety: 
Dose-limiting toxicity (DLT)
Adverse event (AE)
Discontinuing study treatment due to an AE
 
 
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Secondary Endpoint(s)
Objective response is a confirmed CR or PR.
PFS is time from the first dose of study medication to the first 
documented disease progression or death due to any cause, 
whichever occurs first.
OS is time from the first dose of study medication to death 
due to any cause.
ANC in 109/L
PK parameters of navarixin in combination with 
pembrolizumab and PK parameters of pembrolizumab in 
combination with navarixin, including area under the curve 
(AUC) in ng·hr/mL, maximum concentration (Cmax) in 
ng/mL, trough concentration (Ctrough) in ng/mL
Statistical Methods for 
Efficacy/ 
Pharmacokinetic/Pharm
acodynamic Analyses
ORR will be estimated using an exact method based on the 
binomial distribution together with its 95% confidence 
interval (Clopper-Pearson interval). 
Methods for the secondary and exploratory efficacy analyses 
as well as the comparison between the two arms will be
documented in an sSAP.
PK parameters of study medicines will be summarized by 
planned visit and time for each arm. 
ANC and percent change from baseline in ANC will be 
summarized by planned visit and time for each arm
separately.
Treatment Assignment
Participants will be randomized centrally through 
IVRS/IWRS to the 2 arms (doses) of navarixin in 
combination with pembrolizumab, stratified by tumor types.
Statistical Methods for 
Safety Analyses
Summary statistics will be provided for the safety endpoints 
as appropriate (e.g. counts, percentages). Miettinen and 
Nurminen's method will be used to estimate the difference 
between the 2 arms and its 95% confidence interval for 
number of participants with a DLT, number of participants 
with ≥1 AE and number of participants discontinuing study 
treatment due to an AE.
Interim Analyses
An interim safety analysis is planned for each arm after the 
first 10 participants across tumor types have finished at least 
one cycle of therapy in a given arm. An interim futility
analysis is planned for each tumor type in each arm after the 
first 10 participants in each tumor type have finished the first 
tumor assessment. 
Additional 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 timely 
decisions.
 
 
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Multiplicity
No multiplicity adjustment is planned in this Phase 2 trial.
Sample Size and Power 
For the planning purpose, it is assumed that true objective 
response rates of <1% for MSS CRC and 5% for PDL1-
refractory NCSLC and advanced prostate are not considered 
clinically meaningful, whereas true objective response rates 
of 16% for MSS CRC and 20% for PDL1-refractory NCSLC 
and advanced prostate or higher are. With 20 participants in 
each tumor type of each arm under the 2-stage adaptive 
design, the probability that the objective response rate of each 
tumor type is claimed clinical meaningful is <8% when the 
true response rate is not clinically meaningful and >75% 
when the true response rate is clinically meaningful. The total
sample size is 60 participants per arm (20 per each tumor 
type in an arm). No formal hypothesis testing will be 
conducted. 
Responsibility for Analyses/In-House Blinding
10.2
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The trial is open-label, ie, participants, investigators, and Sponsor personnel will be aware of 
participant treatment assignment after each participant is enrolled and treatment is assigned.  
Allocation to treatment will be randomized.
Hypotheses/Estimation
10.3
Objectives and hypotheses of the study are outlined in Section 4 – Objectives/Hypotheses 
and Endpoints.
Analysis Endpoints
10.4
Efficacy/Pharmacokinetics/Pharmacodynamic Endpoints
10.4.1
ORR as assessed by the investigator based on RECIST 1.1 is the primary endpoint. ORR as 
assessed by the investigator based on iRECIST, PFS as assessed by investigator based on 
RECIST 1.1 and iRECIST and OS are the secondary endpoints in this study. A description of 
efficacy measures is provided in Section 9.2 – Efficacy Assessments.
Objective Response rate (ORR) is defined as the proportion of participants who achieve a
confirmed complete response (CR) or partial response (PR). 
Progression-free Survival (PFS) is defined as the time from the first dose of study medication 
to the first documented disease progression or death due to any cause, whichever occurs first.
Overall survival (OS) is defined as the time from the first dose of study medication to death 
due to any cause. 
Pharmacokinetic endpoints include serum concentrations of navarixin and pembrolizumab, as 
well as derived PK parameters.
 
 
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Pharmacodynamic endpoint includes ANC.
Safety Endpoints
10.4.2
The primary safety endpoint is the number/proportion of participants with DLTs (including 
participants with Grade 4 ANC decrease), and AEs, and who discontinue study treatment due 
to AEs.  In addition, safety and tolerability will be assessed by clinical review of all relevant 
parameters including adverse events (AEs), laboratory tests, and vital signs.
A description of safety measures is provided in Section 9.5 - Safety.
Analysis Populations
10.5
Efficacy Analysis Populations
10.5.1
The Full Analysis Set (FAS) population will be used for the analyses of efficacy data in this 
study. It consists of all participants with a baseline scan that demonstrated measurable 
disease by the investigator’s assessment, and who were administered at least 1 dose of study 
medicine.
Safety Analysis Populations
10.5.2
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 participants who received at least 1 dose of 
study treatment. 
The DLT evaluable population includes ASaT participants that meet the criteria for DLT 
evaluability (e.g., finished Cycle 1 without a DLT or experienced a DLT in Cycle 1). See 
Section 5.1.3 for details. 
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Pharmacokinetic Analysis Populations
10.5.3
The Per-Protocol (PP) population will be used for the analysis of PK and PD data in this 
study. The PP population consists of the subset of participants who complied with the 
protocol sufficiently to ensure that their data will be likely to exhibit the effects of treatment, 
according to the underlying scientific model. Compliance includes such considerations as 
exposure to treatment, availability of measurements, and the absence of major protocol 
violations. Any participants or data values excluded from the analyses will be identified, 
along with the reasons for exclusion, in the CSR. At the end of the study, all participants who 
were compliant with the study procedures and have available data from at least 1 treatment 
will be included in the PP analysis dataset.
Statistical Methods
10.6
This section describes the statistical methods that address the primary objectives. Methods 
related to secondary and exploratory objectives as well as the comparison between the t2arms 
will be described in the sSAP. The final analyses will be performed using data from both 
Stage 1 and Stage 2.
 
 
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Statistical Methods for Efficacy Analysis
10.6.1
ORR will be estimated using an exact method based on the binomial distribution together 
with its 95% confidence interval (Clopper-Pearson interval). 
Methods for the secondary and exploratory efficacy analyses as well as the comparison 
between the two arms will be documented in the sSAP.
Statistical Methods for Safety Analysis
10.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
DLTs, AEs, SAEs, laboratory tests, vital signs, ECG measurements, and physical 
examinations.
DLT and adverse events will be summarized by counts and frequencies for each arm.  
Laboratory tests, vital signs, and other safety endpoints will be summarized as appropriate 
(e.g., counts, percentages).
Miettinen and Nurminen's method will be used to estimate the difference between the 2 arms 
and its 95% confidence interval for number of participants with a DLT, number of 
participants with ≥1 AE and number of participants discontinuing study treatment due to an 
AE.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
10.6.3
Demographic and Baseline Characteristics
10.6.3.1
Demographic variables and baseline characteristics will be summarized.
Pharmacokinetic and Pharmacodynamic Modeling Analysis
10.6.3.2
Pharmacokinetic parameters of study medicines will be summarized by planned visit and 
time for each arm separately. 
ANC and percent change from baseline in ANC will be summarized by planned visit and 
time for each arm separately.
Pharmacokinetics and pharmacodynamics modeling analyses will be documented in the 
sSAP.
Interim Analyses
10.7
There is one planned interim safety analysis and one planned interim futility analysis in this 
trial.
An interim safety analysis is planned for each arm after the first 10 participants across tumor 
types have finished at least one cycle of therapy in a given arm. If no more than 3 
participants in the first 10 participants have experienced DTLs during the first cycle in a 
given arm, this arm may be expanded by enrolling 20 additional participants to complete 
Stage 1. Otherwise, this arm may be terminated due to safety concern.
An interim futility analysis is planned for each tumor type in each arm after the first 10
participants in each tumor type have at least 1 post-baseline scan assessment. If 1 or more 
 
 
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responses (ie, ≥10% response rate) are observed in a tumor type within an arm, this tumor 
type may be expanded to enroll at least 10 additional participants in Stage 2. Otherwise, this 
tumor type may be stopped early for futility. If the true response rate is 16%, there is an 82% 
chance to continue the study at the futility evaluation. If the true response rate is 20%, there 
is an 89% chance to continue the study at the futility evaluation.
Additional 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 timely decisions.
Multiplicity
10.8
There will be no multiplicity control in this study.
Sample Size and Power Calculations
10.9
For the planning purpose, it is assumed that true objective response rates of <1% for MSS 
CRC and 5% for PDL1-refractory NCSLC and advanced prostate are not considered 
clinically meaningful, whereas true objective response rates of 16% for MSS CRC and 20% 
for PDL1-refractory NCSLC and advanced prostate or higher are. With 20 participants in 
each tumor type of each arm under the 2-stage adaptive design, the probability that the 
objective response rate of each tumor type is claimed clinical meaningful is less than 8% 
when the true response rate is not clinically meaningful and more than 75% when the true 
response rate is clinically meaningful. The total sample size is 60 participants per arm (20 per
each tumor type in an arm). No formal hypothesis testing will be conducted. Table 8 provides 
the probability that the objective response rate of each tumor type is claimed clinical 
meaningful under different true ORR. Table 9 shows the hypothetical ORR estimates and the 
CI (Clopper-Pearson interval) based on sample size of 20 per tumor type. Due to a small 
sample size, even an observed response rate as high as 30% (6 out of 20) could be coming 
from a true signal as low as 14%. A higher observed responses rate such as 8 out of 20 would 
be more indicative of a true response rate above 20%.
Table 8
Probability That ORR is Claimed as Clinical Interest With 20 Participants in Each 
Tumor Type of Each Arm
Tumor 
Type
ORR as clinical 
meaningful
True 
ORR
Minimum Responses 
that ORR is claimed 
as clinical meaningful
Probability that ORR 
is claimed as 
clinical meaningful
CRC
16%
1%
2
1%
16%
2
77%
NSCLC, 
Prostate
20%
5%
3
7%
20%
3
76%
 
 
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Table 9
The CI of the True ORR Under Different Hypothetical Number of Observed 
Response Scenarios With 20 Participants in Each Tumor Type of Each Arm
Hypothetical number of 
responses (CR or PR)
ORR
90% CI of ORR
80% CI of ORR
2
10%
(1.8%, 28.3%)
(2.7%, 24.5%)
3
15%
(4.2%, 34.4%)
(5.6%, 30.4%)
4
20%
(7.1%, 40.1%)
(9.0%, 36.1%)
5
25%
(10.4%, 45.6%)
(12.7%, 41.5%)
6
30%
(14.0%, 50.8%)
(16.6%, 46.7%)
7
35%
(17.7%, 55.8%)
(20.7%, 51.8%)
8
40%
(21.7%, 60.6%)
(24.9%, 56.7%)
Subgroup Analyses
10.10
Efficacy endpoints will be analyzed by arm for each tumor type. Additional subgroup 
analyses (e.g., by age, gender, and race) may be conducted as needed and will be documented 
in the sSAP. 
Compliance (Medication Adherence)
10.11
Drug accountability data for study treatment will be collected during the trial.  Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
10.12
The extent of exposure will be summarized as duration of treatment in cycles.
11. References
[Acharyya S, Oskarsson 
T, Vanharanta S, Malladi 
S, Kim J 2012]
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Kim J, Morris PG, et al. A CXCL1 paracrine 
network links cancer chemoresistance and 
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04TLN5
[Condamine T, 
Ramachandran I, Youn 
JI, Gabrilovich DI. 2015]
Condamine T, Ramachandran I, Youn JI, 
Gabrilovich DI. Regulation of tumor metastasis by 
myeloid-derived suppressor cells. Annu Rev Med. 
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04TLNB
[David JM, Dominguez 
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C. 2016]
David JM, Dominguez C, Hamilton DH, Palena C. 
The IL-8/IL-8R Axis: A Double Agent in Tumor 
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24;4(3).
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[Gentles, A. J., et al 
2015]
Gentles AJ, Newman AM, Liu CL, Bratman SV, 
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genes and infiltrating immune cells across human 
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04TR0W
 
 
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[Highfill SL, Cui Y, 
Giles AJ, Smith JP, 
Zhang H, Morse E 2014]
Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, 
Morse E, et al. Disruption of CXCR2-mediated 
MDSC tumor trafficking enhances anti-PD1 
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04TLNN
[Kumar V, Patel S, 
Tcyganov E, Gabrilovich 
DI. 2016]
Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The 
Nature of Myeloid-Derived Suppressor Cells in the 
Tumor Microenvironment. Trends Immunol. 2016 
Mar;37(3):208-220.
04TLNX
[Li, L., et al 2015]
Li L, Xu L, Yan J, Zhen ZJ, Ji Y, Liu CQ, et al. 
CXCR2 - CXCL1 axis is correlated with neutrophil 
infiltration and predicts a poor prognosis in  
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04TR2B
[Lu X, Horner JW, Paul 
E, Shang X, Troncoso P, 
Deng P 2017]
Lu X, Horner JW, Paul E, Shang X, Troncoso P, 
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04TLP3
[Saintigny, P., et al 2013]
Saintigny P, Massarelli E, Lin S, Ahn YH, Chen Y, 
Goswami S, et al. CXCR2 expression in tumor cells 
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04TR2N
[Seymour, L., et al 2017]
Seymour L, Bogaerts J, Perrone A, Ford R, 
Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials 
testing immunotherapeutics. Lancet Oncol. 2017 
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04P9RV
[Steele CW, Karim SA, 
Leach JDG, Bailey P, 
Upstill-Goddard R 2016]
Steele CW, Karim SA, Leach JDG, Bailey P, 
Upstill-Goddard R, Rishi L. CXCR2 Inhibition 
Profoundly Suppresses Metastases and Augments 
Immunotherapy in Pancreatic Ductal 
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04TLPZ
 
 
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[Theivanthiran B, DeVito 
NC 2017]
Theivanthiran B, DeVito NC, et al.  A HSP-TLR-
Wnt5a Paracrine Signaling Axis Drives CXCR2 
Ligand Recruitment of Myeloid-derived Suppressor 
Cells and Represents a Novel Adaptive Resistance 
Mechanism to Anti-PD-1 Antibody Therapy.  In: 
Society for Immunotherapy of Cancer 2017 
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04TLQ2
[Wang G, Lu X, Dey P, 
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Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, et 
al. Targeting YAP-Dependent MDSC Infiltration 
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04TLQ0
 
 
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12. Appendices
Appendix 1: Study Governance Considerations
12.1
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participant 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 (eg, 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 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants 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 participants, 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. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC 
approval. For each site, the IRB/IEC and Merck will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance.  
Potential participants 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.  Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants 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 participant 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 participant 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 participants 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 participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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/IEC 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 (eg, 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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Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/IEC) 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 study 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 Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents in 
order to verify worksheet/case report form data.  By signing the consent form, the participant 
agrees to this process.  If study documents will be photocopied during the process of 
verifying worksheet/case report form information, the participant will be identified by unique 
code only; full names/initials will be masked prior to transmission to the Sponsor.
 
 
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study.  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.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and 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 study or its results to those 
registries.
 
 
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Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (eg, 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 study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the study
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study 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 
 
 
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requested by the Sponsor or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the study documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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Appendix 2: Collection and Management of Specimens for Future Biomedical 
12.2
Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 9.9 –
Future Biomedical Research Sample Collection 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.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
Future Biomedical Research sub-study.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the participants on the visit designated in 
the SoA.  If delayed, present consent at next possible Participant Visit.  Consent 
 
 
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forms signed by the participant will be kept at the clinical study site under secure 
storage for regulatory reasons.  
A template of each study 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 participant 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 SoA. In general, if additional blood specimens are being collected for 
Future Biomedical Research, these will usually be obtained at a time when the 
participant is having blood drawn for other study purposes.
4. Confidential Participant 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 participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant 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 study 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 participant 
identifiers and this unique code will be held at the study 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 (eg, 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-study. 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 
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. 
 
 
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If medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant'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 participant 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 study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’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 study 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 
study, the study 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 study 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 Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
 
 
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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 participants.  Participants will not be 
identified by 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 participants diagnosed and treated on Sponsor 
clinical studies for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized and are 
described in the Future Biomedical Research informed consent.
The Sponsor has developed strict security, policies and procedures to address participant 
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: https://www.cancer.gov/publications/dictionaries/cancer-
terms?cdrid=45618
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; Available from:
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
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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Appendix 3: Contraceptive Guidance and Pregnancy Testing
12.3
Definitions 
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with 2 FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in Section 6.1: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
●
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a woman of childbearing potential who is not currently 
pregnant.
o
The following are not acceptable methods of contraception:
▪
Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM).
▪
Male condom with cap, diaphragm, or sponge with spermicide.
▪
Male and female condoms cannot be used together.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10
during the protocol-defined time frame in Section 6.1. 
 
 
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Table 10
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception b, c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b, c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b, c 
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods 
for participants of clinical studies. 
a) Typical use failure rates are higher than perfect-use failure rates (ie, when used 
consistently and correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least 120 days after the last dose of study treatment.
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
 
 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
A urine pregnancy test is to be obtained within 72 hours prior to first dose.
If a urine pregnancy test cannot be confirmed as negative, a serum pregnancy test is required. 
Following initiation of treatment, additional urine/serum pregnancy testing may be 
performed if clinically warranted, and/or as defined by local regulations.
 
 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
12.4
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use in this study.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose of study treatment without any associated clinical symptoms or 
abnormal laboratory results is reported using the terminology “accidental or 
intentional overdose without adverse effect.”
●
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 9.3.5 for additional details.
 
 
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Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has 
not worsened.
●
Refer to section 9.3.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing 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 an MSD product and is documented in the patient’s 
medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
 
 
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events reported in the same manner as SAE
Additional Events which require reporting in the same manner as SAE
●
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.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
 
 
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Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) according to the NCI Common Terminology for 
Adverse Events (CTCAE), version 4.03]. 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.
●
Grade 1: Mild; asymptomatic or mild 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 of hospitalization indicated; disabling; limiting 
self-care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
Assessment of Causality
●
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 product 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:
●
Exposure:  Is there evidence that the participant 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 studies with investigational 
medicinal product)?
 
 
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●
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
●
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; (3) the study is a single-dose drug study); or (4) 
Sponsor's product(s) is/are only used one time.)
●
Rechallenge:  Was the participant 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 study is a single-dose drug study); 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 RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study 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.
●
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. 
 
 
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●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant 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 participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
●
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 (ie, 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.
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor 
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
 
 
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●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or 
secure e-mail of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
 
 
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Appendix 5: Clinical Laboratory Tests 
12.5

The tests detailed in Table 11 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6.0 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 11
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
• Mean Corpuscular Volume (MCV)
• Mean Corpuscular Hemoglobin (MCH)
• %Reticulocytes
White Blood Cell (WBC) 
Count with Differential:
• Neutrophils
• Lymphocytes
• Monocytes
• Eosinophils
• Basophils
Red Blood Cell 
(RBC) Count
Hemoglobin
Hematocrit
Chemistry
Sodium
Potassium
Chloride
Phosphorous
Calcium
Glucose
Bicarbonate / Carbon 
dioxide (CO2)1
Albumin 
Total Protein
Blood Urea 
Nitrogen (BUN)2
Creatinine (and 
measured or calculated 
[per institutional 
standard] creatinine 
clearance [CrCl], if 
creatinine is elevated 
above 1.5 times the 
upper limit of normal)3
Uric Acid
Alanine 
Aminotransferas
e (ALT) / Serum 
Glutamic-
Pyruvic 
Transaminase 
(SGPT)
Aspartate 
Aminotransferase 
(AST) / Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Alkaline Phosphatase
Total Bilirubin (and direct 
bilirubin, if total bilirubin 
is elevated above 1.5 times 
the upper limit of normal)
Routine 
Urinalysis
• Specific Gravity
• pH, Glucose, Protein, Blood, Ketones by Dipstick
• Microscopic Examination (if blood or protein is abnormal)
Other 
Screening 
Tests
• International Normalized Ratio (INR)/Prothrombin Time (PT), Activated Partial 
Thromboplastin Time (aPTT) or Partial thromboplastin time (PTT)4
• Thyroid Function Testing (T4, T3, TSH)5
• Urine Pregnancy Test6
• Serum β-Human Chorionic Gonadotropin (β-hCG)6
• Follicle-Stimulating Hormone (FSH) and Estradiol (as needed in women of non-childbearing 
potential only)7
• Serology (human immunodeficiency virus [HIV] Type 1 and Type 2 antibodies; hepatitis B 
surface antigen [HBsAg]/hepatitis B virus antibody; and hepatitis C virus antibody 
ribonucleic acid (HCV RNA)/hepatitis C antibody)8
 
 
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Laboratory 
Assessments
Parameters
NOTES:
1.
If bicarbonate/CO2 is not done as part of standard of care in your region, these tests do not need to be performed.
2.
Blood urea nitrogen is preferred; if not available, urea may be tested.
3.
Glomerular filtration rate (GFR) can be used in place of CrCl.
4.
Coagulation factors (INR/PT and aPTT or PTT) should be tested as part of screening procedures for all participants. 
Any participant receiving anticoagulant therapy should have coagulation factors monitored closely throughout the 
study.
5.
Total T4 is preferred; if not available, free T4 may be tested. Total T3 is preferred; if not available, free T3 may be 
tested.
6.
Women of childbearing potential only. Urine pregnancy test is preferred. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test is required.
7.
In women <45 years of age, a high FSH in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormone replacement therapy. In the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient.
8.
Testing is at the discretion of the investigator.
Investigators must document their review of each laboratory safety report.
 
 
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Appendix 6: Abbreviations and Trademarks
12.6
Abbreviation/Acronym
Definition
ADA
Anti-drug antibodies
AE
Adverse Event
AJCC
American Joint Committee on Cancer, version 8
ALT 
Alanine aminotransferase
ANC
Absolute Neutrophil Count (Peripheral Blood)
AP
Alkaline phosphatase
aPTT
activated partial thromboplastin time
ASaT
All Subjects as Treated
AST
Aspartate Aminotransferase
AUC
Area Under the Plasma Concentration-Time Curve
BICR
Blinded imaging central review
ß-HCG
Beta-human chorionic gonadotrophin
BUN
Blood urea nitrogen
Cmax
Maximum Observed Plasma Concentration
Cmin
Minimum Observed Plasma Concentration
Ctrough
Trough Observed Plasma Concentration
CNS
Central nervous system
COPD
Chronic Obstructive Pulmonary Disease
CO2
Carbon dioxide
CR
Complete response
CrCl
Creatinine clearance
CRF
Case report form
CRPC
Castration resistant prostate cancer
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte–associated antigen 4
CXCL
Cysteine-X-Cysteine Ligand
CXCR1/2
Cysteine-X-Cysteine Chemokine Receptors 1 and 2
DILI
Drug-induced liver injury
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECI
Event of clinical interest
ECOG
Eastern Cooperative Oncology Group
ELRCXC
Chemokines containing the sequence glutamate-leucine-arginine 
(ELR) immediately preceding the cysteine-x-cysteine (CXC) 
motif
EMT
Epithelial-mesenchymal transition
EOT
End of treatment
FAS
Full Analysis Set
 
 
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Abbreviation/Acronym
Definition
FEV
Forced Expiratory Volume
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
Granulocyte-Colony Stimulating Factor (Filgrastim)
GFR
Glomerular filtration rate
GI
Gastrointestinal
GRO-α
Growth Related Oncogene-Alpha
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HRT
Hormone replacement therapy
IB
Investigator Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
iCPD
iRECIST-confirmed progressive disease
iCR
iRECIST-complete response
IHC
Immunohistochemistry
IL-8
Interleukin-8
INR
International normalized ratio
iPR
iRECIST-partial response
irAE
immune-related adverse event
IRB/IEC
Institutional Review Board/Independent Ethics Committee
iRECIST
Modified response evaluation criteria in solid tumor version 1.1 
for immune-based therapeutics
iSD
iRECIST-stable disease
IUD
Intrauterine device
iUPD
iRECIST-unconfirmed progressive disease
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVRS
Interactive voice-based registration system
IWRS
Interactive web-based registration system
mAb
Monoclonal antibody
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MDSC
Myeloid derived suppressor cell
MK-3475
pembrolizumab
MK-7123
navarixin
MMP-9
Matrix Metallopeptidase 9
MPO
Myeloperoxidase
MRI
Magnetic resonance imaging
MSD
Merck Sharp & Dohme Corp.
MSI
Microsatellite instability
MSI-H
Microsatellite instability-high
 
 
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Abbreviation/Acronym
Definition
MSS CRC
Microsatellite stable colorectal cancer
NCI 
National Cancer Institute 
NSAID
Non-sterioidal anti-inflammatory drug
NSCLC
Non small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PBPK
Physiologically based pharmacokinetic 
PCWG3
Prostate Cancer Working Group 3
PD
Progressive disease
PD-1
Programmed cell death protein 1
PD-(L)1
Programmed death ligand 1
PFS
Progression free survival
PK
Pharmacokinetics
PO
Per os, orally
POC
Proof-of-Concept
PP
Per protocol
PR
Partial response
PSA
Prostate-specific antigen
PT
Prothrombin time
PTT
Partial thromboplastin time
QD
Once Daily
Q3W
Once every 3 weeks
RA
Accumulation Ratio
RBC
Red blood cell
RECIST 1.1
Response evaluation criteria in solid tumor version 1.1
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SCH 527123
Navarixin
SAE
Serious adverse event
SD
Stable disease or standard deviation
SoA
Schedule of Activities
sSAP
supplemental Statistical Analysis Plan
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TBL
Total bilirubin
T1DM
Type 1 diabetes mellitus
TME
Tumor microenvironment
TPS
Tumor Proportion Score
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
WBC
White blood cell
WOCBP
Woman of childbearing potential
 
 
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Appendix 7: Description of the iRECIST Process for Assessment of Disease 
12.7
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
Investigator, the Investigator will decide whether to continue a participant on study treatment 
until repeat imaging is obtained (using iRECIST for participant management (see Table 6
and Figure 3). This decision by the Investigator should be based on the participant’s overall 
clinical condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression 
of disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the Investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the 
original RECIST 1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
 
 
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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline.  All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior 
iUPD time point 

Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
 
 
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Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit (For those studies in which PFS is 
the primary endpoint, add the following: or if RECIST 1.1 PD has not been verified 
centrally), an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 2 and 
submitted to the central imaging vendor.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-
progression. The nadir is always the smallest sum of diameters seen during the 
entire trial, either before or after an instance of pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing 
so for the first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth 
of non-target lesions, taken as a whole.
 
 
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
New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the 
new lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
 
 
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