A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and Immunotherapy Combinations for the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer
Phase: PHASE1
Conditions: Metastatic Castration-resistant Prostate Cancer
Sponsor: Parker Institute for Cancer Immunotherapy

PORTER – Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Amendment 2, Version 1.0 
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Protocol Title:  A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers 
and Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-
resistant Prostate Cancer 
Protocol Number:  PICI0033 
Amendment Number:  2 
Compound Number:  Not applicable 
Short Title:  Platform Study for Prostate Researching Translational Endpoints Correlated to 
Response to Inform Use of Novel Combinations (PORTER) 
Sponsor Name and Legal Registered Address:   
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 415-985-7311 
 
Regulatory Agency Identifying Number(s):  
IND NUMBER: 139269 (CDER) and 18853 (CBER) 
EudraCT NUMBER:  Not applicable 
Approval Date:  Final Protocol: 07 December 2018  
 
Amendment 1: 24 January 2019 
 
Amendment 2: 30 April 2019 
 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to Parker Institute for Cancer 
Immunotherapy. Any unauthorized copying or use of this document is prohibited. 

PORTER – Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Amendment 2, Version 1.0 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by Parker Institute for Cancer 
Immunotherapy. 
• 
Not to implement any changes to the protocol without written agreement from Parker 
Institute for Cancer Immunotherapy and prior review and written approval from the 
Institutional Review Board or Independent Ethics Committee except where necessary to 
eliminate an immediate hazard to participants. 
• 
That I am thoroughly familiar with the appropriate use of the study drug(s), as described 
in the protocol cohort appendices and any other information provided by Parker Institute 
for Cancer Immunotherapy including, but not limited to, the current Investigator’s 
Brochure(s). 
• 
That I am aware of, and will comply with, the International Conference on 
Harmonisation for Good Clinical Practice (GCP) and all applicable regulatory 
requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about the 
study drugs, the Parker Institute for Cancer Immunotherapy study protocol, and of their 
study-related duties and functions as described in the protocol. 
• 
That I agree that persons debarred from conducting or working on clinical studies by any 
court or regulatory agency will not be allowed to conduct or work on studies for the 
Parker Institute for Cancer Immunotherapy or for a partnership in which the Parker 
Institute for Cancer Immunotherapy is involved, and that I will immediately disclose in 
writing to the Parker Institute for Cancer Immunotherapy if any person who is involved 
in the study is debarred, or if any proceeding for debarment is pending. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  
 
 
  
 

PORTER – Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Amendment 2, Version 1.0 
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Amendment(s) to the Protocol 
Text revisions resulting from the amendment(s) are incorporated in the synopsis and body of the 
Protocol Amendment. Major changes to the protocol are summarized below. 
Key Revisions in Amendment 1 (24 January 2019) 
Section # and Name 
Description of Change 
Statistical Considerations 
9.5.2 Cohort Expansion Rules 
Added safety criteria that would inform the decision to proceed to Stage 2 
of each immunotherapy combination. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial 
changes for clarity. 
Appendix B-1 
Reordered the management algorithms to match the order on the 
appendix cover page. 
 
Key Revisions in Amendment 2 (30 April 2019) 
Section # and Name 
Description of Change 
Study Design 
3 Objectives and Endpoints 
Updated primary and secondary endpoints to align with statistical 
analyses for the study cohorts. 
4.1 Overall Design 
Added clarification that all cohorts may be enrolling simultaneously. 
Study Interventions 
6.5.2 Prohibited Therapy 
Provided clarification regarding herbal and natural remedies allowing for 
use of marijuana and derivatives for treatments of cancer or cancer 
treatment-related symptoms. 
Statistical Considerations 
9.2 Sample Size Determination 
Added language and table defining confidence intervals for adverse event 
rates in determining ORR. 
9.3.1.2 Secondary Efficacy 
Endpoints 
Updated language for PSA response endpoint to better define who will 
not be evaluable in the study population. 
9.5.1 Cohort Stopping Criteria 
Added language detailing conditions under which an ad hoc Safety 
Assessment Committee meeting will be held and what stopping criteria 
will be used for cohorts in the event of serious adverse events. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial 
changes for clarity. 
 

PORTER – Parker Institute for Cancer Immunotherapy 
Protocol PICI0033 Amendment 2, Version 1.0 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................10 
LIST OF APPENDIX TABLES ....................................................................................................10 
LIST OF FIGURES .......................................................................................................................10 
1 
PROTOCOL SUMMARY .................................................................................................11 
1.1 
SYNOPSIS .............................................................................................................11 
1.2 
SCHEMA ...............................................................................................................14 
1.3 
SCHEDULE OF ACTIVITIES..............................................................................14 
2 
INTRODUCTION .............................................................................................................18 
2.1 
STUDY RATIONALE ..........................................................................................18 
2.2 
BACKGROUND ...................................................................................................18 
2.3 
BENEFIT/RISK ASSESSMENT ..........................................................................20 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................20 
4 
STUDY DESIGN...............................................................................................................22 
4.1 
OVERALL DESIGN .............................................................................................22 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ...........................................23 
4.3 
JUSTIFICATION FOR DOSE ..............................................................................23 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION ........................................23 
4.5 
END OF STUDY DEFINITION ...........................................................................24 
5 
STUDY POPULATION ....................................................................................................24 
5.1 
INCLUSION CRITERIA.......................................................................................24 
5.2 
EXCLUSION CRITERIA .....................................................................................25 
5.3 
LIFESTYLE CONSIDERATIONS .......................................................................25 
5.4 
SCREEN FAILURES ............................................................................................25 
6 
STUDY INTERVENTION ................................................................................................25 
6.1 
STUDY INTERVENTION(S) ADMINISTERED ................................................25 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................25 
6.3 
RANDOMIZATION AND BLINDING................................................................26 
6.3.1 
Intervention Assignment .........................................................................26 
6.3.2 
Blinding ...................................................................................................26 

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6.4 
STUDY INTERVENTION COMPLIANCE .........................................................26 
6.5 
CONCOMITANT THERAPY...............................................................................26 
6.5.1 
Permitted Therapy ...................................................................................27 
6.5.2 
Prohibited Therapy ..................................................................................27 
6.6 
DOSE MODIFICATIONS (ESCALATION/TITRATION/ OTHER) ..................28 
6.7 
INTERVENTION AFTER THE END OF THE STUDY .....................................28 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................28 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ........................................28 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY ........29 
7.3 
LOST TO FOLLOW-UP .......................................................................................30 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................30 
8.1 
EFFICACY ASSESSMENTS ...............................................................................31 
8.1.1 
Laboratory Assessments of Clinical Activity ..........................................32 
8.2 
SAFETY ASSESSMENTS ....................................................................................32 
8.2.1 
Medical History and Demographic Data .................................................33 
8.2.2 
Physical Examinations .............................................................................33 
8.2.3 
Vital Signs ...............................................................................................33 
8.2.4 
Electrocardiograms ..................................................................................33 
8.2.5 
Clinical Safety Laboratory Assessments .................................................34 
8.2.5.1 
Local Laboratory Assessments ..............................................34 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..............................35 
8.3.1 
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ......................................................36 
8.3.1.1 
Events Requiring Expedited Reporting to the Sponsor .........36 
8.3.2 
Follow-up Event Reporting .....................................................................37 
8.3.3 
Method of Eliciting Adverse Event Information .....................................37 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................38 
8.3.5 
Pregnancy ................................................................................................38 
8.3.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs .......................................................................................39 
8.3.7 
Adverse Events of Special Interest ..........................................................39 
8.3.8 
Sponsor Contact Information ..................................................................39 

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8.3.8.1 
Emergency Medical Contacts ................................................39 
8.3.8.2 
Safety Reporting Contacts .....................................................40 
8.4 
TREATMENT OF OVERDOSE ...........................................................................40 
8.5 
PHARMACOKINETICS .......................................................................................40 
8.6 
ANTI-DRUG ANTIBODIES ................................................................................40 
8.7 
BIOMARKERS .....................................................................................................40 
8.7.1 
Genetics ...................................................................................................42 
8.7.2 
Exploratory Biomarkers ..........................................................................42 
8.7.3 
Sample Collection for Long-term Future Biomedical Research .............43 
8.7.3.1 
Overview of Long-term Future Biomedical Research ..........43 
8.7.3.2 
Sample Collection .................................................................43 
8.7.3.3 
Withdrawal from Long-term Sample Storage .......................43 
8.7.3.4 
Protection of Data Privacy and Data Generation ..................44 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ..........44 
9 
STATISTICAL CONSIDERATIONS...............................................................................44 
9.1 
STATISTICAL HYPOTHESIS .............................................................................44 
9.2 
SAMPLE SIZE DETERMINATION ....................................................................44 
9.3 
STATISTICAL ANALYSES ................................................................................45 
9.3.1 
Efficacy Analyses ....................................................................................46 
9.3.1.1 
Primary Efficacy Endpoint ....................................................46 
9.3.1.2 
Secondary Efficacy Endpoints ..............................................46 
9.3.1.3 
Exploratory Efficacy Endpoints ............................................47 
9.3.2 
Safety Analyses .......................................................................................48 
9.3.3 
Other Analyses ........................................................................................48 
9.3.3.1 
Pharmacokinetic Analysis .....................................................48 
9.3.3.2 
Biomarker Analysis ...............................................................48 
9.3.3.3 
Anti-Drug Antibody Analysis ...............................................48 
9.4 
POPULATIONS FOR ANALYSIS .......................................................................49 
9.5 
INTERIM ANALYSES .........................................................................................49 
9.5.1 
Interim Safety Monitoring .......................................................................49 
9.5.2 
Cohort Expansion Rules ..........................................................................50 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....52 

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10.1 
APPENDIX 1: REGULATORY, ETHICAL AND STUDY OVERSIGHT 
CONSIDERATIONS .............................................................................................52 
10.1.1 
Compliance with Laws and Regulations .................................................52 
10.1.2 
Institutional Review Board or Independent Ethics Committee ...............52 
10.1.3 
Financial Disclosure ................................................................................53 
10.1.4 
Informed Consent ....................................................................................53 
10.1.5 
Data Protection ........................................................................................54 
10.1.6 
Dissemination of Clinical Study Data .....................................................54 
10.1.7 
Administrative Structure .........................................................................54 
10.1.8 
Data Quality Assurance ...........................................................................55 
10.1.9 
Source Documentation ............................................................................55 
10.1.10 Study and Site Closure ............................................................................56 
10.1.11 Site Inspections ........................................................................................57 
10.1.12 Retention of Records ...............................................................................57 
10.1.13 Publication Policy and Protection of Trade Secrets ................................57 
10.2 
APPENDIX 2: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ..................................................................................58 
10.3 
APPENDIX 3: RECIST CRITERIA (VERSION 1.1) WITH MODIFICATIONS 
AS RECOMMENDED BY PCWG3 .....................................................................59 
10.3.1 
Measurability of Tumor at Baseline ........................................................59 
10.3.2 
Tumor Response Evaluation ....................................................................60 
10.3.2.1 
Baseline Documentation of Target and Nontarget Lesions ...60 
10.3.2.2 
Evaluation of Target Lesions .................................................60 
10.3.2.3 
Evaluation of Nontarget Lesions ...........................................61 
10.3.2.4 
New Lesions ..........................................................................61 
10.3.2.5 
Evaluation of Overall Response ............................................61 
10.3.3 
Modifications for mCRPC as Recommended by PCWG3 ......................62 
10.3.3.1 
PCWG3 Recommendations with Regard to Baseline Disease 
Assessments ...........................................................................63 
10.3.3.2 
PCWG3 Recommendations with Regard to Measuring 
Outcomes and Reporting .......................................................64 
10.4 
APPENDIX 4: CLINICAL LABORATORY TESTS ...........................................69 
10.5 
APPENDIX 5: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES 
FOR RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ........70 

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Protocol PICI0033 Amendment 2, Version 1.0 
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10.5.1 
Definitions ...............................................................................................70 
10.5.1.1 
Definition of AE ....................................................................70 
10.5.1.2 
Definition of SAE ..................................................................71 
10.5.1.3 
Definition of Unexpected AE ................................................72 
10.5.1.4 
Definition of Treatment-emergent AE ..................................73 
10.5.2 
Additional Events Reported in the Same Manner as an SAE .................73 
10.5.3 
Recording AEs and SAEs ........................................................................74 
10.5.4 
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ....................................................................................................78 
10.5.5 
Additional Reporting Considerations ......................................................79 
10.6 
APPENDIX 6: CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION ..........................................................................83 
10.6.1 
Definitions ...............................................................................................83 
10.6.1.1 
Woman of Childbearing Potential .........................................83 
10.6.2 
Contraception Guidance ..........................................................................83 
10.6.3 
Collection of Pregnancy Information from Male Participants with 
Partners who Become Pregnant ...............................................................85 
10.7 
APPENDIX 7: GENETICS ...................................................................................86 
10.8 
APPENDIX 8: LISTS OF TERMINOLOGY AND ABBREVIATIONS .............87 
10.8.1 
List of Terminology .................................................................................87 
10.8.2 
List of Abbreviations ...............................................................................87 
10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY ....................................91 
11 
REFERENCES ..................................................................................................................92 
 

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LIST OF TABLES 
Table 1: 
Schedule of Activities ............................................................................................15 
Table 2: 
Objectives and Corresponding Endpoints ..............................................................20 
Table 3: 
Laboratory Tests Sent to the Study Site Local Laboratory for Analysis of Disease-
related Endpoints ...................................................................................................32 
Table 4: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of Safety
................................................................................................................................35 
Table 5: 
Confidence Intervals for the True Proportion of Adverse Events .........................45 
Table 6: 
Populations for Analysis ........................................................................................49 
 
 
LIST OF APPENDIX TABLES 
Appendix Table 1: 
Response Based on Evaluation of Target Lesions at Each Assessment ..60 
Appendix Table 2: 
Response Based on Evaluation of Nontarget Lesions at Each Assessment
 
61 
Appendix Table 3: 
Evaluation of Overall Response at Each Assessment .............................61 
Appendix Table 4: 
Criteria for Progression at Trial Entry by Disease Manifestation ...........63 
Appendix Table 5: 
Suggested Outcome Measures for Clinical Trials in Metastatic Prostate 
Cancer: Report by Disease Manifestation..............................................................66 
Appendix Table 6: 
Highly Effective Contraceptive Methods for Partner Use ......................84 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schema.........................................................................................................14 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol Title: 
A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and 
Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-resistant 
Prostate Cancer 
Short Title: 
Platform Study for Prostate Researching Translational Endpoints Correlated to Response to 
Inform Use of Novel Combinations (PORTER) 
Rationale: 
This study is designed to test multiple clinical hypotheses and mechanistically-defined 
combinations to evaluate the safety and efficacy of immunotherapy combination in participants 
with metastatic castration-resistant prostate cancer (mCRPC) who have received prior secondary 
androgen receptor signaling inhibitor therapy (eg, abiraterone, enzalutamide, apalutamide). 
Key Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of each immunotherapy 
combination in participants with mCRPC. 
• Incidence and severity of AEs. 
Secondary 
 
• To determine the ORR of each immunotherapy 
combination in participants with measurable 
mCRPC. 
• To determine the DCR ≥ 9 months of each 
immunotherapy combination in participants with 
measurable mCRPC. 
• To evaluate the rPFS of each immunotherapy 
combination in participants with mCRPC. 
• To estimate the OS of each immunotherapy 
combination in participants with mCRPC. 
• ORR: A composite endpoint where response is 
defined as a participant meeting at least one of the 
following: 
o CTC response: Change from unfavorable (≥ 5 
cells/7.5 mL of blood) to favorable (≤ 4 cells/7.5 
mL of blood). Participants with a baseline CTC 
value < 5 cells/7.5 mL of blood will not be 
evaluated for this criterion. 
o PSA response: Confirmed PSA response is 
defined as ≥ 50% reduction in PSA from baseline, 
with a repeat assessment confirming the result at 
least 3 weeks later. Participants without a baseline 
and at least 2 post-baseline PSA assessments will 
not be evaluated for this criterion. 
o Confirmed response of CR or PR by objective 
radiographic disease assessment using modified 
RECIST version 1.1 (ie, CR or PR and no 
progression in bone per the PCWG3; Scher et al., 
2016). Per RECIST, to be assigned a best overall 

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response of CR or PR, changes in tumor 
measurements must be confirmed by repeat 
assessments that should be performed no less than 
4 weeks after the criteria for response are first 
met. Participants who received at least 1 dose of 
the combination study intervention or component 
of the combination but do not have RECIST 
assessment for any reason will be counted as not 
responding. 
• DCR at 9 months: Defined as CR, PR, or SD 
for 9 months as best response by PCWG3-modified 
RECIST 1.1. Participants who received at least 1 
dose of the study intervention combination or 
component of the combination but do not have 
RECIST assessment for any reason will be counted 
as not responding. 
• rPFS: Defined as time from initiation of study 
intervention to the first objective evidence of 
radiographic progression, or death due to any cause 
(whichever occurs first). 
• OS: Defined as the time from initiation of study 
invention until death due to any cause. 
• OS rate at 12 months. 
AE(s) = adverse event(s); CR = complete response; CTC = circulating tumor cells; DCR = disease control rate; 
ECOG = Eastern Cooperative Oncology Group; mCRPC = metastatic castration-resistant prostate cancer; 
ORR = objective response rate; OS = overall survival; PCWG3 = Prostate Cancer Clinical Trials Working Group 3; 
PR = partial response; PSA = prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; 
rPFS = radiographic progression-free survival; SD = stable disease 
 
Overall Design: 
This is an open-label, non-randomized, exploratory platform protocol designed to assess the 
safety and antitumor activity of multiple immunotherapy combinations in participants with 
mCRPC who have received prior therapy. The platform study will consist of 2 stages: Stage 1, an 
initial stage to evaluate safety, biomarkers, and clinical activity of a combination and Stage 2, an 
expanded cohort, when warranted, based on the safety, clinical activity, and/or biomarker results 
from Stage 1. The Sponsor intends to modify and/or add new combinations to the protocol as 
data emerge from this and other trials. 
Participants must provide consent for archival tissue from a prior biopsy or surgery for prostate 
cancer and must consent to baseline and on-treatment biopsies, if medically feasible. Participants 
will be assigned to receive one of the enrolling combination study interventions and will be 
monitored for safety and response.  
The duration of immunotherapy combination study intervention will be dependent on the 
combination administered and will continue for the duration described in the cohort appendix for 
each respective combination, unless the participant: is no longer clinically benefiting (NLCB; as 

PORTER – Parker Institute for Cancer Immunotherapy 
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evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); 
experiences any toxicity meeting specified discontinuation criteria (as described in the cohort 
appendix for each respective combination) or unacceptable toxicity in the best clinical discretion 
of the treating physician (ie, Investigator discretion); reaches the maximum duration of study 
intervention; or withdraws consent. Participants will be followed for up to 2.5 years from the 
time of the initiation of study intervention (see Follow-up). Depending on the combination 
administered, participants who are clinically benefiting, as defined by the Investigator at the end 
of the study treatment period, may have post-study access to the immunotherapy combination 
received during the study after written agreement from the Medical Monitor. 
Number of Participants: 
The study is not intended or powered for hypothesis testing. The study is intended to provide 
preliminary estimates of adverse event (AE) rates, response rates, effect sizes, and confidence 
intervals (CIs) to aid the design of later studies. A sample size of approximately 15 participants 
per combination intervention will provide these preliminary estimates while limiting exposure. 
An additional approximately 15 participants will be enrolled in Stage 2, if the cohort is 
expanded. 
Intervention Groups and Duration: 
This is not a randomized study. Assignment to one of the immunotherapy combinations will be 
made by the Investigator using his/her best clinical discretion based on the participant’s medical 
history and disease status and knowledge of the available immunotherapy combinations open for 
enrollment. 
The dose and schedule selected will be described in the cohort appendix for each respective 
combination (eg, Appendix Cohort A, Appendix Cohort B, etc.). The duration of immunotherapy 
combination study intervention will be dependent on the combination administered. Depending 
on the combination administered, participants who are clinically benefiting as defined by the 
Investigator at the end of the study may have post-study access to the immunotherapy 
combination after agreement from the Medical Monitor. 
Follow-up: 
For up to 2.5 years from the initiation of study intervention, participants in the follow up phase 
will be contacted by telephone by the site personnel every 3 months to collect alternate 
anticancer therapy information and determine survival status. 
Participants will be followed for a up to 2.5 years from the time of the initiation of study 
intervention unless the consent is withdrawn. All participants will be followed for safety for at 
least 100 days after discontinuation of study intervention. 

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Depending on the combination administered, participants who are clinically benefiting, as 
defined by the Investigator at the end of the study treatment period, may have post-study access 
to the immunotherapy combination received during the study after agreement from the Medical 
Monitor. 
A participant will be considered lost to follow-up if he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site (see Section 7.3). 
Data Monitoring Committee:  This study will use a Safety Assessment Committee (SAC) of 
genitourinary (GU) oncologists and immuno-oncologists, who will meet regularly with the 
Sponsor to monitor safety on an ongoing basis (see Section 9.5.1). 
1.2 
SCHEMA 
The study schema is depicted in Figure 1. 
Figure 1: 
Study Schema 
 
 
1.3 
SCHEDULE OF ACTIVITIES 
The Schedule of Activities (SOA) shown in Table 1 provides a general overview of the types and 
timing of the tests and procedures that will be performed in this study. The combination-specific 
tests and procedures, as well as the timing, will be described in the cohort appendix for each 
respective combination and will supersede the general overview provided here.   

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Table 1: 
Schedule of Activities 
Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: Immunotherapy Combination Treatment 
End of 
Treatmentb 
Follow up 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Onward 
Day 
 
To be determined based on immunotherapy combination 
Refer to the cohort appendix for each respective combination for 
details on combination-specific timing 
14 - 28 days 
after last 
dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
± 3 
± 3 
± 3 
± 3 
± 7 
± 10 
± 14 
Informed consentd 
X 
 
 
 
 
 
 
 
 
Review of I/E criteria 
X 
 
 
 
 
 
 
 
 
Medical and cancer history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (see Section 
8.2.3) 
X 
X 
X 
X 
X 
X 
X 
 
 
Body weighte 
X 
 
 
X 
 
X (every 
3 cycles) 
X 
 
 
Hematology (see Table 4) 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
X 
 
Clinical chemistry (see 
Table 4) 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
 
Prostate-specific antigen 
X 
X 
X 
X 
X 
X 
X 
X 
 
Testosterone level 
X 
 
 
 
 
 
 
 
 
12-lead ECGg 
X 
 
X 
 
X 
 
 
 
 
Circulating tumor cellsh 
 
Xf 
Xf 
Xf 
Xf 
Xf 
X 
 
 
cfDNA (blood)i 
X 
 
Xf 
 
Xf 
 
X 
 
 
Circulating soluble 
analytes/PK/ADAj 
X 
Xf 
Xf 
Xf 
Xf, 
 
X 
 
 
Blood immune biomarkersj 
X 
Xf 
Xf 
Xf 
Xf 
 
X 
 
 
Archival tumor tissue 
X 
 
 
 
 
 
 
 
 

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Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: Immunotherapy Combination Treatment 
End of 
Treatmentb 
Follow up 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Onward 
Day 
 
To be determined based on immunotherapy combination 
Refer to the cohort appendix for each respective combination for 
details on combination-specific timing 
14 - 28 days 
after last 
dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
± 3 
± 3 
± 3 
± 3 
± 7 
± 10 
± 14 
Tumor biopsyk 
X 
 
X 
 
 
 
X (at PD 
[optional])k 
 
 
Stool collectionl 
X 
 
X 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
All AEs/AESIs/SAEs will be collected for at least 100 days after the last dose of study interventionm 
 
Immunotherapy 
combination administrationn 
 
Refer to the cohort appendix for each respective combination for 
details on study intervention administration 
 
 
 
Radiographic disease 
assessment 
X 
Per PCWG3 guidelines: Every 8 to 9 weeks (± 1 week) for first 24 weeks, and every 12 weeks (± 1 week) 
thereafter until radiographic PD or start of subsequent therapy. 
Refer to the cohort appendix for each respective combination for cohort-specific details 
Review of alternate 
anticancer therapyo 
 
 
 
 
 
 
 
X 
X 
Follow-up for overall 
survival 
 
 
 
 
 
 
 
X 
X 
ADA = anti-drug antibodies; AE(s) = adverse event(s); AESI(s) = adverse event(s) of special interest; cfDNA = cell-free deoxyribonucleic acid; ECG = electrocardiogram; 
ECOG  = Eastern Cooperative Oncology Group; EOT = end of treatment; I/E = inclusion/exclusion; PCWG3 = Prostate Cancer Clinical Trials Working Group 3; PD = progressive 
disease; PD-1 = programmed cell death 1; PK = pharmacokinetics; Q3M = every 3 months; SAE(s) = serious adverse event(s) 
a Tests/procedures performed as standard of care prior to obtaining informed consent and within 28 days prior to the first day of study intervention administration do not have to 
be repeated at screening. 
b The End of Treatment Visit will be completed following the last dose of study intervention, either at completion of the on-treatment phase or at early discontinuation. 
c For up to 2.5 years from the initiation of study intervention, participants in the follow up phase will be contacted by the site to collect alternate anticancer therapy information 
and determine survival status. 
d Informed consent must be obtained prior to any study-specific procedures and may be obtained prior to the 28-day screening window. 
e Body weight may be required more frequently for study interventions using weight-based dosing. Combination-specific frequency will be provided in the cohort appendix for 
each respective combination. 
f Blood samples should be collected prior to administration of any study intervention.  
g 12-Lead ECG will be collected at screening, Cycle 2 and Cycle 4. 

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h Circulating tumor cells will be collected at baseline (ie, Day 1 of Cycle 1 prior to study intervention administration), Day 1 of each cycle (prior to study intervention 
administration), and EOT. 
i cfDNA (blood) will be collected at baseline (ie, screening visit prior to study intervention administration), Day 1 of Cycle 2 and Cycle 4, and EOT. 
j Circulating soluble analytes, PK and ADA blood sample, and/or blood immune biomarkers will be collected at baseline (ie, screening and/or Day 1 of Cycle 1 prior to study 
intervention administration), prior to study intervention administration on Day 1 of Cycles 2-4, and EOT. 
k Participants will undergo 2-3 tumor biopsies: prior to beginning study intervention (ie, baseline biopsy, mandatory for all participants, including those with bone only disease if 
medically feasible), and during treatment (ie, on-treatment biopsy during Cycle 2, if medically feasible). On-treatment biopsy should occur as early as possible after the second 
dose (Day 2 – Day 10 of Cycle 2); however, any on treatment biopsy after Day 1 of Cycle 2 will be accepted. An optional biopsy may be obtained at the time of disease 
progression, including from participants who respond and subsequently progress. Every attempt should be made for the on-treatment biopsies to be taken from the same lesion as 
the pre-treatment biopsy when feasible. 
l Stool will be collected at screening and during Cycle 2, if possible. Otherwise, any on-treatment stool sample will be acceptable. The stool sample may be collected at the clinic 
or at the participant’s home. 
m All SAEs will be collected from the time the participant signs informed consent. Prior to initiation of study intervention, only SAEs that are related to a protocol-mandated 
intervention, including those that occur prior to the assignment of study procedures should be reported. All AEs, including AESIs (as applicable and as defined in the cohort 
appendix for each respective combination), will be collected from the start of study intervention. All AEs/AESIs/SAEs will be collected for at least 100 days after the last dose of 
study intervention. Refer to Section 8.3 for details regarding safety reporting for this study. 
n The duration of the immunotherapy combination will be dependent on the combination administered, and will continue for the duration described in the cohort appendix for each 
respective combination, unless the participant: is no longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); 
experiences any toxicity meeting specified discontinuation criteria (as described in the cohort appendix for each respective combination) or unacceptable toxicity in the best 
clinical discretion of the treating physician; reaches the maximum duration of study intervention; or withdraws consent. 
o Collection of information related to any post-study intervention alternate anticancer therapy. 

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2 
INTRODUCTION 
Immunotherapy is an attractive strategy for patients with advanced prostate cancer because it has 
the potential to lead to durable responses and is generally better tolerated. However, the only 
United States (US) Food and Drug Administration (FDA) approved immunotherapy for prostate 
cancer to date is sipuleucel-T, an autologous cellular vaccine designed to stimulate an immune 
response targeting prostatic acid phosphatase (PAP) (Kantoff et al., 2010). The only phase 3 
randomized controlled trial of immune checkpoint blockade, with ipilimumab in metastatic 
castration-resistant prostate cancer (mCRPC) patients after docetaxel, failed to meet its primary 
endpoint of overall survival (OS; Kwon et al., 2014). Early phase studies of programmed cell 
death 1 (PD-1) blockade in advanced malignancies have not demonstrated clinical activity in 
advanced prostate cancer (Topalian et al., 2012). More recently, anti-PD-1 therapy has been 
shown to have limited activity as a single agent in patients with mCRPC who have programmed 
cell death ligand 1 (PD-L1) expression and tumor-infiltrating leukocytes, including one patient 
with microsatellite instability (MSI) and mismatch repair (MMR) deficiency (Graff et al., 2016). 
Thus, there is a critical need to develop new approaches to make immunotherapy available to 
patients with mCRPC. Using an approach similar to the multi-arm, multi-stage platform trial 
(STAMPEDE), which has provided an innovative trial design for testing new treatment 
approaches against the standard of care for prostate cancer, including mCRPC (Sydes et al, 2018; 
Parmar et al., 2017), a platform study of immunotherapy combinations is proposed. A recently-
opened, ongoing study at the National Cancer Institute is investigating a similar platform design 
for immunotherapy combinations to treat mCRPC (QuEST1; Redman et al., 2018). With the 
development of new immuno-oncology therapies demonstrating enhanced effects within the 
immune system, opportunities for combination clinical trials in the area of antitumor immune 
response in mCRPC have increased. Given the lack of clinical benefit of immunotherapy in 
mCRPC and the multiple hypotheses around the immune evasion and resistance mechanisms, an 
adaptive platform clinical study is well suited to advance the understanding to inform treatment 
of this underserved patient population. 
2.1 
STUDY RATIONALE 
This study is designed to evaluate multiple clinical hypotheses and mechanistically-defined 
combinations to evaluate the safety and efficacy of immunotherapy combinations in participants 
with mCRPC who have received prior secondary androgen receptor signaling inhibitor therapy 
(eg, abiraterone, enzalutamide, apalutamide). 
2.2 
BACKGROUND 
Prostate cancer remains the most commonly diagnosed malignancy, accounting for 19% of 
newly-diagnosed cancer in men in the US. Despite recent decreases, it is estimated that 

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approximately 164,690 new cases will be diagnosed in 2018, and 29,430 men are estimated to 
die of prostate cancer in 2018. Prostate cancer is the second leading cause of cancer death among 
men in the US (Siegel et al., 2018). The 5-year survival for early stage (stage I, II, III) prostate 
cancer is almost 100%, however, almost one-third of the early stage patients will recur with 
metastatic disease (stage IV). For patients with metastatic disease, 5-year survival rates decrease 
to about 30% (Siegel et al., 2018; McNeel et al., 2016). Androgen deprivation therapy (ADT) is 
the mainstay of initial therapy for metastatic disease. Although prostate cancer usually initially 
responds to ADT, resistance frequently develops and progresses to mCRPC. Despite the 
approval of several mCPRC therapies in the past few years, including androgen signaling 
inhibitors, chemotherapy, radiopharmaceutical, and cancer vaccine, currently available 
treatments remain inadequate to manage mCPRC. 
Immunotherapy has changed the landscape of cancer treatments for a number of malignancies, 
resulting in marked clinical benefit in patients with cancers, including metastatic melanoma, non-
small cell lung cancer and renal cell carcinoma. In 2010, the first cancer vaccine, sipuleucel-T 
(Provenge®) was approved for prostate cancer; however, subsequent efforts to demonstrate 
effectiveness of immunotherapies in prostate cancer have been disappointing. While the immune 
responsiveness of prostate tumors has been contested for nearly 30 years, more recent evidence 
suggests prostate cancer is an immunologically recognized disease (Drake, 2010). Intratumoral 
natural killer (NK) cells and macrophages have been observed, and both CD4+ and CD8+ T cells 
that recognize prostate-cancer-specific antigens have been found in tumor sites, as well as in 
peripheral immune cells (Lee and Gujar, 2018). Furthermore, the detection of prostate-specific 
autoantibodies in patients with prostate cancer has strengthened the argument for the 
immunogenicity of prostate cancer (Di Lorenzo et al., 2011). Thus, there is preclinical and 
clinical evidence that prostate could be susceptible to immune-based therapy approaches. 
Notwithstanding, there have been several notable immunotherapy failures in prostate cancer, 
including in clinical trials with novel vaccine-based approaches and immune checkpoint 
inhibitors, including anti-PD-1, anti-PD-L1, and anti- cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) (Kwon et al., 2014; Beer et al., 2017; Brahmer et al., 2010; Topalian et al., 
2012). Thus, prostate cancer has been characterized as an immunologically unresponsive, or 
“cold,” tumor with PD-L1 expression in a minority of tumors (Martin et al., 2015). As a “cold” 
tumor, the immunosuppressive microenvironment may contribute to the low responses to 
immunotherapy in prostate cancer (Patel and Fong, 2018), including low mutational burden 
(Alexandrov et al., 2013), low abundance of intratumoral T cells (Flammiger et al. 2012), and 
low cytolytic activity of NK cells (Pasero et al., 2016), as well as a high accumulation of 
regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor (Miller et 
al., 2006; Lopez-Bujanda and Drake, 2017). Comprehensive correlative studies of prostate 
cancer in a window of opportunity study also demonstrated that elevated expression of PD-L1 

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and VISTA (V-domain Ig suppressor of T cell activation) on macrophages may contribute to the 
resistance to checkpoint inhibitors (Gao et al., 2017). Therefore, treatment-based approaches that 
address these mechanisms of immune evasion through novel combination therapies using novel 
vaccine strategies, alleviating immunosuppression in the tumor microenvironment and new 
immune agents, or identifying immune-responsive patient subsets may enable effective 
immunotherapy treatment approaches for mCRPC with high unmet medical need. 
2.3 
BENEFIT/RISK ASSESSMENT 
The benefit/risk assessment is dependent on the combination administered and will be described 
in the cohort appendix for each respective combination (eg, Appendix Cohort A, Appendix 
Cohort B, etc.).  
3 
OBJECTIVES AND ENDPOINTS 
The study objectives and endpoints are listed in Table 2. 
Table 2: 
Objectives and Corresponding Endpoints 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of each immunotherapy 
combination in participants with mCRPC. 
• Incidence and severity of AEs. 
Secondary 
 
• To determine the ORR of each immunotherapy 
combination in participants with measurable 
mCRPC. 
• To determine the DCR ≥ 9 months of each 
immunotherapy combination in participants with 
measurable mCRPC. 
• To evaluate the rPFS of each immunotherapy 
combination in participants with mCRPC. 
• To estimate the OS of each immunotherapy 
combination in participants with mCRPC. 
• ORR: A composite endpoint where response is 
defined as a participant meeting at least one of the 
following: 
o CTC response: Change from unfavorable (≥ 5 
cells/7.5 mL of blood) to favorable (≤ 4 cells/7.5 
mL of blood). Participants with a baseline CTC 
value < 5 cells/7.5 mL of blood will not be 
evaluated for this criterion. 
o PSA response: Confirmed PSA response is 
defined as ≥ 50% reduction in PSA from baseline, 
with a repeat assessment confirming the result at 
least 3 weeks later. Participants without a baseline 
and at least 2 post-baseline PSA assessments will 
not be evaluated for this criterion. 
o Confirmed response of CR or PR by objective 
radiographic disease assessment using modified 
RECIST version 1.1 (ie, CR or PR and no 
progression in bone per the PCWG3; Scher et al., 
2016). Per RECIST, to be assigned a best overall 
response of CR or PR, changes in tumor 
measurements must be confirmed by repeat 
assessments that should be performed no less than 
4 weeks after the criteria for response are first 
met. Participants who received at least 1 dose of 
the combination study intervention or component 

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of the combination but do not have RECIST 
assessment for any reason will be counted as not 
responding. 
• DCR at 9 months: Defined as CR, PR, or SD 
for 9 months as best response by PCWG3-modified 
RECIST 1.1. Participants who received at least 1 
dose of the study intervention combination or 
component of the combination but do not have 
RECIST assessment for any reason will be counted 
as not responding. 
• rPFS: Defined as time from initiation of study 
intervention to the first objective evidence of 
radiographic progression, or death due to any cause 
(whichever occurs first). 
• OS: Defined as the time from initiation of study 
invention until death due to any cause. 
• OS rate at 12 months. 
Exploratory 
 
• To evaluate tumor and immune biomarkers and their 
association with treatment outcome (antitumor 
activity and/or safety). 
• To evaluate the PK of the components of the 
immunotherapy combination. 
• To evaluate the immunogenicity (ADA) of the 
components of the immunotherapy combination. 
• Association of tumor and immune biomarkers from 
tissue, blood, and/or stool with clinical outcomes, 
including ORR, DCR, rPFS, and tolerability. 
Biomarkers to be studied will be chosen based on 
the immunotherapy combination. 
• Molecular characterization of CTC and evaluation of 
percent change from baseline. 
• Enumeration of CTC ≥ 1 at baseline with conversion 
to CTC0 on treatment. 
• PSA: 
o Percent change in PSA from baseline at 12 weeks. 
o Maximum change in PSA at any point after 
initiation of study intervention. 
o Time to PSA progression defined as the time 
from study treatment initiation to the date that a 
≥ 25% increase and absolute increase of ≥ 2 
ng/mL above the nadir (or baseline value for 
participants who did not have a decline in PSA) in 
PSA. The increase must be confirmed by a second 
consecutive assessment conducted at least 3 
weeks later. 
• Sparse PK analysis. 
• Presence of ADA against biologic components of 
each immunotherapy combination. 
ADA = anti-drug antibodies; AE(s) = adverse event(s); CR = complete response; CTC = circulating tumor cells; 
CTC0 = a measure of zero CTC; DCR = disease control rate; ECOG = Eastern Cooperative Oncology Group; 
mCRPC = metastatic castration-resistant prostate cancer; ORR = objective response rate; OS = overall survival; 
PCWG3 = Prostate Cancer Clinical Trials Working Group 3; PK = pharmacokinetics; PR = partial response; 
PSA = prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; rPFS = radiographic 
progression-free survival; SD = stable disease 

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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is an open-label, non-randomized, exploratory platform study designed to assess the safety 
and antitumor activity of multiple immunotherapy combinations in participants with mCRPC 
who have received prior therapy. The platform study will consist of 2 stages: Stage 1, an initial 
stage to evaluate safety, biomarkers, and clinical activity of the combination and Stage 2, an 
expanded cohort, when warranted, based on the safety, clinical activity, and/or biomarker results 
from Stage 1. The Sponsor intends to modify and/or add new combinations to the protocol as 
data emerge from this and other trials. 
This study will be conducted in participants with histologically-confirmed mCRPC that is 
measurable or non-measurable by Prostate Cancer Clinical Trials Working Group 3 (PCWG3)-
modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Participants with brain 
metastases are excluded unless treated and stable by imaging for at least 4 weeks prior to the first 
dose of study intervention. Participants must have received prior secondary androgen receptor 
signaling inhibitor therapy (eg, abiraterone, enzalutamide, apalutamide) and may have received 
prior chemotherapy for mCRPC. Participants must consent to baseline and on-treatment biopsies, 
if medically feasible. A minimum of 7 participants in each cohort must have a non-bone 
metastatic lesion that can be biopsied. Participants must have adequate organ and hematologic 
function and acceptable performance status. 
After consenting to participate in this clinical trial, participants will be screened for enrollment. 
If they meet all inclusion criteria and do not meet exclusion criteria, they will be referred for a 
pre-treatment biopsy of a metastatic lesion. Participants must also provide consent for archival 
tissue from a prior biopsy or surgery for prostate cancer. Each participant will be assigned per 
the Investigator’s discretion to receive one of the enrolling combination study interventions. 
Participants will be monitored for safety and efficacy. An on-treatment biopsy is required when 
medically feasible, ideally after the second dose of the immunotherapy combination. An optional 
biopsy may be obtained at the time of disease progression, including from participants who 
respond and subsequently progress. The on-treatment biopsies should be taken from the same 
lesion as the pre-treatment biopsy when feasible. 
Approximately 15 participants, including a minimum of 7 with a non-bone metastatic lesion that 
can be biopsied, will be enrolled in each immunotherapy combination cohort in Stage 1. 
Enrollment of participants in each cohort may occur simultaneously. An additional 
approximately 15 participants, including a minimum of 7 with a non-bone metastatic lesion, will 
be enrolled in Stage 2, if the cohort is expanded. 

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The duration of immunotherapy combination study intervention will be dependent on the 
combination administered and will continue for the duration described in the cohort appendix for 
each respective combination, unless the participant is no longer clinically benefiting (as 
evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); 
experiences any toxicity meeting specified discontinuation criteria (as described in the cohort 
appendix for each respective combination) or unacceptable toxicity in the best clinical discretion 
of the treating physician; reaches the maximum duration of study intervention; or withdraws 
consent. Participants will be followed for a up to 2.5 years from the time of the initiation of study 
intervention. Depending on the combination administered, participants who are clinically 
benefiting, as defined by the Investigator at the end of the study treatment period, may have post-
study access to the immunotherapy combination received during the study after agreement from 
the Medical Monitor. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The scientific rationale for this study is provided in Section 2. The scientific rationale for the 
individual cohorts will be provided in the cohort appendix for each respective combination. 
4.3 
JUSTIFICATION FOR DOSE 
The dose and schedule selected will be described in the cohort appendix for each respective 
combination (eg, Appendix Cohort A, Appendix Cohort B, etc.). The duration of immunotherapy 
combination study intervention will be dependent on the combination administered. 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION 
Accumulating evidence indicates that a minority of patients treated with immunotherapy may 
derive clinical benefit from continued treatment despite initial evidence of disease progression 
(Wolchok et al., 2009). The PCWG3 introduced the concept of treatment beyond progression 
(where clinical benefit by one or more disease manifestations is being observed) as clinical 
measure for outcome in prostate cancer (Scher et al., 2016). The PCWG3 recommendation 
included a reporting metric of no longer clinically benefiting (NLCB), defined as the date and 
specific reason(s) therapy was ultimately discontinued, to allow individualized provider-patient 
decisions to discontinue or continue treatment. 
Therefore, participants receiving immunotherapy combinations in this study will be permitted to 
continue study intervention beyond initial Investigator-assessed disease progression (according 
to PCWG3-modified RECIST 1.1) provided all of the following criteria are met: 
• Absence of symptoms and signs indicating rapid disease progression, including decline in 
performance status, and confirmation of disease status required 

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• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
• Participant is adequately consented regarding the potential risks of continuation of 
ineffective therapy/failure to initiate effective alternative therapy, if any 
• Written agreement from the Medical Monitor. 
 
The assessment of clinical benefit should consider whether the participant is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 
All decisions to continue treatment beyond initial progression must be discussed with the 
Medical Monitor and written agreement from the Medical Monitor should be documented in the 
study records. 
Participants should discontinue study intervention upon evidence of further progression, defined 
as an additional ≥ 10% increase in tumor burden from the time of initial progression (including 
all target lesions and new measurable lesions, or unequivocal progression of non-target lesions). 
New lesions are considered measurable at the time of initial progression if the diameters are ≥ 10 
mm (except for pathological lymph nodes, which must have a short axis of ≥ 15 mm). Any new 
lesion considered non-measurable at the time of initial progression may become measurable and 
therefore included in the tumor burden measurement if the diameter increases to ≥ 10 mm 
(except for pathological lymph nodes, which must have an increase in short axis to ≥ 15 mm). 
4.5 
END OF STUDY DEFINITION 
The end of this study is defined as the date when the last visit of the last participant occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is received 
from the last participant, whichever occurs later.  
The total length of each study cohort, from screening of the first participant to the end of the 
cohort, will depend on the study intervention administered and will be described in the cohort 
appendix for each respective combination. 
5 
STUDY POPULATION 
This study will enroll participants with mCRPC. Eligibility criteria are provided in the cohort 
appendix for each respective combination (eg, Appendix Cohort A, Appendix Cohort B, etc.). 
5.1 
INCLUSION CRITERIA 
Inclusion criteria are provided in the cohort appendix for each respective combination. 

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5.2 
EXCLUSION CRITERIA 
Exclusion criteria are provided in the cohort appendix for each respective combination. 
5.3 
LIFESTYLE CONSIDERATIONS 
Lifestyle considerations or restrictions, if required, will be provided in the cohort appendix for 
each respective combination (eg, Appendix Cohort A, Appendix Cohort B, etc.). 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study. 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 serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
The dose and schedule selected will be described in the cohort appendix for each respective 
combination (eg, Appendix Cohort A, Appendix Cohort B, etc.). The duration of immunotherapy 
combination study intervention will be dependent on the combination administered. 
Administration of study intervention will be performed in a monitored setting in which there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
The Investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may dispense and/or administer study intervention. All study intervention must be stored in 
a secure, environmentally controlled, and monitored (manual or automated) area in accordance 

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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 intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manuals. 
6.3 
RANDOMIZATION AND BLINDING 
6.3.1 
Intervention Assignment 
This is not a randomized study. Assignment to one of the immunotherapy combinations will be 
made by the Investigator using his/her best clinical discretion based on the participant’s medical 
history and disease status and knowledge of the available immunotherapy combinations open for 
enrollment. 
6.3.2 
Blinding 
This is an open-label trial; therefore, the Sponsor, Investigator, and participant will know the 
study intervention administered. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Study intervention compliance will be described in the cohort appendix for each respective 
combination as compliance measures will be dependent on how the immunotherapy combination 
is administered. 
6.5 
CONCOMITANT THERAPY 
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates (or indicated as ongoing, as 
applicable) 
• Dosage information including dose, route of administration, and frequency 
 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 

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6.5.1 
Permitted Therapy 
Concomitant medications or treatments (eg, acetaminophen/paracetamol, diphenhydramine) may 
be prescribed if considered necessary for adequate prophylactic or supportive care except for 
those medications identified as “excluded” in Section 6.5.2 or in the cohort appendix for each 
respective combination (for combination-specific excluded medications). 
All concomitant medication will be recorded on the electronic case report form (eCRF), 
including all prescription, OTC and intravenous (IV) medications and fluids. If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date should also be 
included on the eCRF. 
All concomitant medications received within 28 days prior to the first dose of study intervention 
and 100 days after the last dose of study intervention should be recorded. Concomitant 
medications administered after 100 days after the last dose of study intervention should be 
recorded for SAEs and adverse events of special interest (AESIs) (as applicable and as defined in 
the cohort appendix for each respective combination). 
6.5.2 
Prohibited Therapy 
The medications listed below are prohibited during the study. The Sponsor must be notified if a 
participant receives any of these during the study. 
• Any concurrent systemic chemotherapy, immunotherapy, biologic, hormonal treatment or 
radiotherapy (except palliative radiotherapy) not specified in this protocol or subsequent 
amendments. Concurrent use of hormones for noncancer-related conditions are permitted. 
o Exception: Androgen deprivation therapy. Participants are required to maintain 
castrate-level testosterone (< 50 ng/dL) with a gonadotropin-releasing hormone 
(GnRH) agonist or antagonist ± antiandrogen. Participants without history of bilateral 
orchiectomy are required to remain on ADT. 
• Any concurrent investigational anticancer therapy not specified in this protocol or 
subsequent amendments. 
• Anti-CTLA-4, anti-PD-L1, or anti-PD-1 agents through 100 days after the last dose of 
study intervention, except for agents that are not part of the immunotherapy 
combinations. 
• Immunosuppressive medications at chronic systemic doses > 10 mg/day prednisone (or 
equivalent) within 28 days before the first dose (note: hormone replacement therapy 
(HRT), such as thyroxine, insulin, or physiologic corticosteroid replacement therapy ≤ 10 
mg of prednisone/day for adrenal or pituitary insufficiency, etc. is not considered a form 
of systemic treatment). A temporary course of steroids (ie, contrast allergy, chronic 

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obstructive pulmonary disease) may be permitted, depending on the duration and dose, 
after discussion and agreement with the Medical Monitor. 
• Live attenuated vaccines within 30 days prior to the first dose of study intervention and 
through 180 days after the last dose of study intervention. Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, 
yellow fever, rabies, bacille Calmette-Guerin (BCG), and typhoid vaccine. 
• Any botanical preparation (eg herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Use of marijuana and its derivatives for 
treatment of symptoms related to cancer or to cancer treatment are permitted. 
 
6.6 
DOSE MODIFICATIONS (ESCALATION/TITRATION/ 
OTHER) 
Specific anticipated or potential toxicities associated with the administration of the study 
intervention, as well as the measures taken intended to avoid or minimize such toxicity in this 
trial, are described in the cohort appendix for each respective combination. 
Refer to the Investigator’s Brochure (IB) for the individual components of each combination for 
complete summaries of safety information. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY 
Participants who are clinically benefiting as defined by the Investigator at the end of the study 
may have post-study access to the immunotherapy combination after agreement from the 
Medical Monitor. 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Participants must discontinue study intervention if they experience any of the following: 
• Intolerable toxicity related to study intervention, including the development of an adverse 
event (AE) determined by the Investigator to be unacceptable even with the participant’s 
potential response to intervention due to the severity of the event 
• Any medical condition that may jeopardize participant safety if he continues to receive 
the study intervention 
• Use of another anticancer therapy (see Section 6.5.2 and as described in the cohort 
appendix for each respective combination, as applicable) 
• Symptomatic deterioration attributed to disease progression 

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• Progression of disease: Either unequivocal symptomatic progression necessitating a 
change in therapy in the opinion of the treating physician or confirmed radiographic 
progression as defined by cross-sectional imaging per PCWG3-modified RECIST 1.1 
(see Appendix 3) in the absence of clinical benefit (refer to Section 4.4). 
 
Participants have the right to voluntarily withdraw from study intervention at any time for any 
reason. In addition, the Investigator has the right to withdraw a participant from study 
intervention at any time. Reasons for withdrawal from the study intervention may include, but 
are not limited to, the following: 
• Investigator or Sponsor determines it is in the best interest of the participant 
• Participant noncompliance 
 
The primary reason for study intervention discontinuation should be documented on the 
appropriate eCRF page. 
The visit at which disease assessment shows progressive disease (PD) may be used as the 
treatment discontinuation visit if it occurs within 28 (± 7) days after the last dose of study 
intervention. Participants who discontinue study intervention for any reason other than PD or 
loss of clinical benefit should have an end of treatment discontinuation assessment as outlined in 
the SOA (see Section 1.3). All participants should continue follow-up as outlined in the SOA. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM 
STUDY 
The total length of study participation, from participant screening to the end of study, is expected 
to be approximately 31 months.  
When study intervention is discontinued, participants should have an end of treatment 
discontinuation assessment followed up by an assessment 14-28 days after the last dose of study 
intervention as outlined in the SOA (see Section 1.3). Information on survival follow-up and new 
anticancer therapy will be collected every 3 months for up to 2.5 years from the initiation of 
study intervention until any of the following occurs: 
• Death 
• Loss to follow-up 
• Study termination by the Sponsor 
• Participant requests to be withdrawn from follow-up 
 

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A participant may withdraw consent at any time and discontinue study intervention and further 
participation in the study. This request must be documented in the source documents and signed 
by the Investigator. The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent. Participants who withdraw consent will not be followed for any reason 
after consent has been withdrawn. However, the study staff may use a public information source 
(eg, county records) to obtain information about survival status only. 
Other reasons for discontinuation of study intervention and/or participation in a follow-up phase 
of the study may include death, AEs, physician decision, protocol deviation, eligibility not met, 
progressive disease. A participant is considered to have completed all phases of the study as 
defined in the cohort appendix for each respective combination, including the lead-in phase, as 
applicable, the treatment phase, and the safety and survival follow-up after last dose of study 
intervention. 
The primary reason for withdrawal from study should be documented on the appropriate eCRF 
page. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 
• Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Please see Section 1.3 for the schedule of activities and procedures to be performed during the 
study. All activities should be performed and documented for each participant in the order of the 
SOA. Participants will be closely monitored for safety and tolerability throughout the study. 

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Participants should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable as deemed by the Principal 
Investigator (PI). 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
administrative disruption that precludes the visit, the visit should be scheduled on the nearest 
feasible date. The time between doses must not be less than described in the cohort appendix for 
each respective combination.  
Collection of any non-safety-related data or participant samples may be terminated by the 
Sponsor at any time if further collection of such data or samples is also not related to the study’s 
primary or secondary objectives. The decision to discontinue any data collection will be 
communicated to the sites and Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) by means of a memorandum and will not require a protocol amendment. 
8.1 
EFFICACY ASSESSMENTS 
Participants will undergo tumor assessments as designated in the SOA (see Section 1.3) 
regardless of dose delays, until loss of clinical benefit as determined by the Investigator (unless 
the participant withdraws consent, or the Sponsor terminates the study). All participants who 
discontinue study intervention for reasons other than disease progression (eg, AEs) will continue 
tumor assessments for up to 2.5 years from initiation of study intervention or until study 
completion, death, disease progression, loss to follow-up, withdrawal of consent, or study 
termination, whichever occurs first. At the Investigator’s discretion, tumor assessments may be 
repeated at any time if PD is suspected. 
Measurable and evaluable lesions should be assessed and documented at screening. Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 28 
days prior to the first dose of study intervention do not have to be repeated at screening. 
Screening assessments must include computerized tomography (CT) scans (with IV contrast 
unless contraindicated and oral contrast as appropriate per institutional standards) of the chest, 
abdomen, and pelvis. A spiral CT scan of the chest may be obtained but is not a requirement. If a 
CT scan with contrast is contraindicated (ie, in participants with contrast allergy or impaired 
renal clearance), a non-contrast CT scan of the chest maybe performed and magnetic resonance 
imaging (MRI) scans of the abdomen and pelvis should be performed. If the participant has a 
known history of brain metastases or is symptomatic in the opinion of the Investigator, scans of 
the head should be obtained. 
If a CT scan for a tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards for a full contrast diagnostic 
CT scan. 

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Bone scans (technetium-99m [TC-99m]) should be performed at screening if clinically indicated. 
If bone metastases are present at screening and cannot be seen on CT or MRI scans, or if 
clinically indicated, TC-99m bone scans should be repeated when complete response (CR) is 
identified in target disease or when progression in bone is suspected. 
CT scans of the neck or extremities should also be performed if clinically indicated and repeated 
throughout the study if there is evidence of disease at screening.  
All measurable and evaluable lesions should be reassessed at each subsequent tumor evaluation. 
The same radiographic procedures used to assess disease sites at screening should be used for 
subsequent tumor assessments (eg, same contrast protocol for CT scans). 
Response will be assessed by the Investigator using PCWG3-modified RECIST 1.1 (see 
Appendix 3). Assessments should be performed by the same evaluator, if possible, to ensure 
internal consistency across visits. Results must be reviewed by the Investigator before dosing at 
the next cycle. 
Radiographic confirmation of disease progression is required by repeat scans 4 – 6 weeks 
following any scan suggesting disease progression. Participants will remain on study and 
continue to receive study intervention during this time. 
8.1.1 
Laboratory Assessments of Clinical Activity 
Samples for the following laboratory assessments of clinical activity and hormone levels will be 
sent to the study site local laboratory for analysis:  
Table 3: 
Laboratory Tests Sent to the Study Site Local Laboratory for Analysis of 
Disease-related Endpoints 
Profile 
Laboratory Test 
Clinical activity 
PSA 
Hormone levels 
testosterone 
PSA = prostate-specific antigen 
 
8.2 
SAFETY ASSESSMENTS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and AESIs, 
performing protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. Planned timing for all safety assessments is provided in the SOA 
(Section 1.3).  
Certain types of events require immediate reporting to the Sponsor, as described in Section 
8.3.1.1. 

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8.2.1 
Medical History and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history (including 
stage, date of diagnoses, and prior cancer therapies and procedures), reproductive status, 
smoking history, use of alcohol, and drugs of abuse, will be recorded at baseline. In addition, all 
medications (eg, prescription drugs, OTC drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by the participant within 28 days prior to the first dose of study 
intervention will be recorded. Demographic data may include age, sex, and race/ethnicity. 
8.2.2 
Physical Examinations 
A complete physical examination should be performed at screening and should include an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems. Any 
abnormality identified at baseline should be recorded on the Medical History eCRF page. 
Eastern Cooperative Oncology Group (ECOG) performance status (see Appendix 2) should be 
assessed per the SOA in Section 1.3. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be recorded in 
participant notes. New or worsened clinically significant abnormalities should be recorded as 
AEs on the Adverse Event eCRF page. 
8.2.3 
Vital Signs 
Vital signs should include measurements of respiratory rate, pulse rate, systolic and diastolic 
blood pressure, pulse oximetry (required only at screening), and temperature as outlined in the 
SOA (Section 1.3). Vital signs collected at the screening visit should be recorded on the eCRF. 
For each visit thereafter, only vital signs obtained prior to the study intervention administration 
as outlined in the SOA or during an AE (eg, temperature or event of fever) should be recorded on 
the eCRF. All vital signs collected per protocol should be documented in the participant’s 
medical record. 
Vital signs should be measured within 15 minutes prior to and after the administration of study 
intervention. Vital signs may be measured, if medically indicated, at other time points. 
8.2.4 
Electrocardiograms 
A single electrocardiogram (ECG) recording will be obtained at baseline, as outlined in the SOA 
(Section 1.3) and may be obtained at unscheduled time points as indicated.  
All ECG recordings must be performed using an institutionally-approved ECG. Lead placement 
should be as consistent as possible. ECG recordings should be performed after the participant has 
been resting in a supine position for at least 10 minutes. 

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For safety monitoring purposes, the Investigator must review, sign, and date all ECG tracings. 
ECG tracings will be kept as part of the participant's medical record. The Investigator’s 
assessment (ie, normal, abnormal [not clinically significant], or abnormal [clinically significant]) 
should be recorded on the appropriate eCRF page. Any morphologic waveform changes or other 
ECG abnormalities should be documented on the eCRF page. 
8.2.5 
Clinical Safety Laboratory Assessments 
Clinical laboratory tests will be performed at the local institution as described in the SOA 
(Section 1.3). 
The Investigator must review the laboratory report, document this review, and designate results 
as being not clinically significant of clinically significant. Clinically significant abnormal 
findings are those for which an action was taken (ie, providing fluid, transfusion, medication, 
and/or holding, delaying, or discontinuing study intervention) or those that are not associated 
with the underlying disease, unless judged by the Investigator to be more severe than expected 
for the participant's condition. Clinically significant changes occurring during the study should 
be documented on the appropriate eCRF. The laboratory reports much be filed with the source 
documents. 
In the event of a Grade 3 or Grade 4 laboratory toxicity, the test for the abnormal laboratory 
value should be repeated until the event is resolved to ≤ Grade 1 or baseline. 
8.2.5.1 
Local Laboratory Assessments 
Samples for the laboratory tests in Table 4 will be sent to the study site’s local laboratory for 
analysis: 

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Table 4: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Safety 
Profile 
Laboratory Test 
Hematology 
RBC count 
hemoglobin 
hematocrit 
WBC count with automated differential (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
platelet count 
manual differential, if clinically indicated 
Clinical Chemistry 
(Serum or Plasma) 
sodium 
potassium 
chloride 
bicarbonate 
glucose 
BUN or urea 
creatinine 
total protein 
albumin 
calcium 
total bilirubin 
alkaline phosphatase 
ALT 
AST 
LDH 
TSH (T3 and FT4 should be checked if TSH is outside the normal range) 
coagulation assessments (PT, PTT, INR)a 
Urinalysis 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
INR  = international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; TSH = thyroid stimulating hormone; WBC = white blood cell 
a Coagulation assessment not required during treatment phase unless indicated 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The definitions of an AE or SAE can be found in Appendix 5. 
Investigators will seek information on AEs at each participant contact until at least 100 days after 
the last dose of study intervention. AEs reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant's legally authorized representative) or noted by study 
personnel, will be recorded in the participant’s medical record and on the Adverse Event eCRF 
page. If the AE is determined to meet seriousness criteria, the event will be reported as an SAE 
on the study-specific SAE Report Form (SAERF) within 24 hours of awareness. Seriousness 
criteria is defined in Appendix 5. 

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The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE, AESI (as applicable), or SAE and remain 
responsible for following up AEs that are serious, considered related to the study intervention or 
study procedures, or that caused the participant to discontinue the study intervention (see 
Appendix 5). 
8.3.1 
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information 
All SAEs will be collected from the time the participant signs informed consent until at least 
100 days after the last dose of study intervention. Prior to initiation of study intervention, only 
SAEs that are related to a protocol-mandated intervention, including those that occur prior to the 
assignment of study procedures (eg, screening invasive procedures, such as biopsies) should be 
reported. After obtaining informed consent, but prior to initiation of study intervention, other 
medical occurrences will be recorded as medical history. 
All AEs, including AESIs (as applicable), will be collected from the start of study intervention 
until at least 100 days after the last dose of study intervention.  
If the Investigator learns of any SAE, including a death, at any time after the end of the AE 
reporting period, and he/she considers the event to be reasonably related to the study intervention 
or study participation, the Investigator must promptly notify the Sponsor or its designee. The 
Investigator should report these events directly to the Sponsor or its designee, either by faxing or 
emailing the SAERF. 
The method of recording and reporting AEs, AESIs (as applicable), and SAEs are provided in 
Appendix 5. The procedure for submitting SAE reports is provided in Section 8.3.8.2. 
The method of reporting all deaths is provided in Appendix 5. 
8.3.1.1 
Events Requiring Expedited Reporting to the Sponsor 
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to 
address potential new risks in a clinical trial. The Investigator must report such events to the 
Sponsor immediately; under no circumstances should reporting take place more than 24 hours 
after the Investigator becomes aware of the event. The following is a list of events that the 
Investigator must report to the Sponsor within 24 hours of becoming aware of the event, 
regardless of relationship to study intervention: 
• All SAEs (defined in Appendix 5) 
• Protocol-specified AEs, including AESI as applicable, as defined in the cohort appendix 
for each respective combination 

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• Pregnancy (female partners of participants; see Section 8.3.5 for details on reporting 
requirements) 
• Occurrence of overdose (see Section 8.4 for details on reporting requirements) 
 
All reported safety data will be evaluated on a regular basis as described in Section 9.5.1. 
8.3.2 
Follow-up Event Reporting 
The Investigator must report new significant follow-up information for the events requiring 
expedited reported (see Section 8.3.1.1) to the Sponsor immediately (ie, within 24 hours of 
awareness). New significant information includes the following: 
• New signs or symptoms or a change in the diagnosis 
• Significant new diagnostic test results 
• Change in causality based on new information 
• Change in the event’s outcome, including recovery 
• Additional narrative information on the clinical course of the event 
• Hospital notes, diagnostic results, and/or discharge summary 
• Death certificate/Autopsy report 
 
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and AESIs (as applicable and as defined 
in the cohort appendix for each respective combination), will be followed through the follow-up 
phase of the study. Events will be followed until event resolution or death, the participant is lost 
to follow-up (as defined in Section 7.3), or the participant withdraws consent. Further 
information on follow-up procedures is provided in Appendix 5. 
For SAEs, and AESIs, the Sponsor or a designee may follow up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details and outcome information (eg, 
from hospital discharge summaries, consultant reports, autopsy reports) in order to perform an 
independent medical assessment of the reported case. If follow up information is obtained during 
a monitoring visit, follow up documentation must be reported to the Parker Institute for Cancer 
Immunotherapy Pharmacovigilance Group. 
8.3.3 
Method of Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all participant evaluation time points. Open-ended and non-leading verbal 
questioning of the participant is the preferred method to inquire about AE occurrences. Examples 

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of non-directive questions include: “How have you felt since your last clinic visit?”, “Have you 
had any new or changed health problems since you were last here?” 
8.3.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met (see Section 8.3.1.1). Investigators must also 
comply with local requirements for reporting SAEs to the IRB/IEC or other local health 
authorities. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators. The Parker Institute for Cancer 
Immunotherapy Pharmacovigilance Group will report SAEs to regulatory authorities, the overall 
PI, partner companies, and the IRB, as appropriate. The process for such reporting, including 
contact information and specific instructions for reporting to each of these organizations, is 
described in the Safety Monitoring Plan (a separate document). 
Expectedness will be assessed using the IB(s) as reference documents. Reporting requirements 
will also be based on the Investigator's assessment of causality and seriousness, with allowance 
for upgrading by the Sponsor as needed. 
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 specific safety-related information (eg, SUSAR notification; 
summary or listing of SAEs) from the Sponsor will review and then file it along with the IB and 
will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female partners of participants will be collected after the start of 
study intervention and until at least 7 terminal half-lives after the last dose. Female partners of 
childbearing potential will be instructed to immediately inform the Investigator if they become 
pregnant during the study or within 7-half-lives after the last dose of each component of study 
intervention. If a pregnancy is reported, the Investigator should inform the Sponsor within 24 
hours of becoming aware of the pregnancy and should follow the procedures outlined in 
Appendix 6. Abnormal pregnancy outcomes that meet serious criteria (eg, spontaneous abortion, 
fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 

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A clinical trial-specific Pregnancy Reporting Form should be completed and submitted 
immediately to the Parker Institute for Cancer Immunotherapy Pharmacovigilance Group, either 
by faxing or by scanning and emailing the form using the fax number or email address provided 
to Investigators (see Section 8.3.8.2). Pregnancy should not be recorded on the Adverse Event 
eCRF page. The Investigator should counsel the participant’s partner, discussing the risks of the 
pregnancy and the possible effects on the fetus. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any SAEs associated with the pregnancy (eg, an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the SAERF. In addition, the Investigator 
will submit a clinical trial-specific Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available. 
8.3.6 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
Progression of the cancer under study, as judged by the Investigator, is not considered a 
reportable event. If, upon further review by the Investigator, the event is determined as not being 
associated with underlying progression of disease, it must be reported as an SAE within 24 hours 
to the Parker Institute for Cancer Immunotherapy Pharmacovigilance Group as described in 
Section 8.3.8.2. 
8.3.7 
Adverse Events of Special Interest 
Selected non-serious and serious AEs known as AESIs are those of scientific and medical 
concern specific to the study intervention or program for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor is appropriate. These events will be identified 
in the cohort appendix for each respective combination. 
8.3.8 
Sponsor Contact Information 
8.3.8.1 
Emergency Medical Contacts 
Parker Institute for Cancer Immunotherapy Medical Monitor: 
Medical Monitor: 
Joyson Karakunnel, MD, MSc, FACP 
 
Parker Institute for Cancer Immunotherapy  
 
1 Letterman Drive, Ste. D3500 
 
San Francisco, CA 94080 
 
jkarakunnel@parkerici.org 
Telephone No.: 
(415) 539-3165 (Office; United States) 

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8.3.8.2 
Safety Reporting Contacts 
The following contact information should be used when submitting safety-related paper forms 
(SAERF and Pregnancy Report Form) as described in Appendix 5 for SAEs and other reportable 
safety events. These forms should be completed and submitted to the Sponsor immediately (ie, 
no more than 24 hours after becoming aware of the event), by faxing to the Parker Institute for 
Cancer Immunotherapy Pharmacovigilance Group at:  415-610-5471 within 24 hours of event 
awareness. If technical issues arise, please contact Parker Institute for Cancer Immunotherapy 
Pharmacovigilance Group immediately at 415-930-4414, and the form may be scanned and 
emailed to safety@parkerici.org. 
Parker Institute for Cancer Immunotherapy Pharmacovigilance Group: 
• Pharmacovigilance Fax Number:  415-610-5471 
• Pharmacovigilance Email:  safety@parkerici.org 
• Pharmacovigilance Telephone Number:  415-930-4414 
 
8.4 
TREATMENT OF OVERDOSE 
Overdose is defined as any dose higher than the dose specified to be administered in accordance 
with the protocol, whether accidental or intentional. 
The Investigator must immediately notify the Parker Institute for Cancer Immunotherapy 
Pharmacovigilance Group of any occurrence of overdose with study intervention.  
All overdoses should be reported as an SAE with the safety criteria of “other important 
medical event.” Details of signs and symptoms, clinical management, and outcome should be 
reported, if applicable. Overdoses should also be captured as protocol deviations. 
The PI has the obligation to report the deviations to the IRB/IEC. 
8.5 
PHARMACOKINETICS 
Sparse pharmacokinetic (PK) blood sampling may be collected as described in the cohort 
appendix for each respective combination, as applicable. 
8.6 
ANTI-DRUG ANTIBODIES 
Anti-drug antibodies (ADA) to specific biologic components of study intervention may be 
evaluated as described in the cohort appendix for each respective combination, as applicable. 
8.7 
BIOMARKERS 
The exploratory biomarker objective of this study is to assess tumor tissue and circulating 
soluble factors, including, but not limited to, deoxyribonucleic acid (DNA), ribonucleic acid 

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(RNA), enzymes, growth factors, cytokines, antibodies, and immune and tumor cells in tissue 
and blood, and their association with treatment outcome. Additionally, microbiome profiles may 
be evaluated from stool samples.  Evaluation of baseline levels and/or post-treatment changes 
from baseline may be performed to determine association with clinical outcomes, including 
clinical response or lack of response, as well as study intervention tolerability. 
• Collection of samples for biomarker research is part of this study. The following samples 
for biomarker research are required and will be collected from all participants in this 
study as specified in the SOA (Table 1) and process in accordance with the laboratory 
manual: 
o Blood 
o Peripheral blood mononuclear cells (PBMCs) 
o Circulating tumor cells (CTC) 
o DNA 
o RNA 
o Tumor tissue biopsy (archival tumor tissue and fresh biopsies at intervals 
specified in Section 4.1) 
o Stool 
• Samples may be tested for genetic analysis on tumor, stool, and blood samples, including, 
but not limited to, assays on circulating free DNA, DNA from tumor, stool, blood, and/or 
immune cells and T cell receptor sequencing may be performed.  This research may 
evaluate whether genetic variations correspond with outcomes of treatment. If genetic 
variation is found to predict efficacy or AEs, the data might inform optimal use of 
therapies in cancer patients. Circulating soluble analytes may be assessed that may 
include but are not limited to immune cytokines, growth factors, antibodies, and/or 
markers associated with immune characteristics and activation or cancer. Additionally, 
tumor and blood samples will be collected before and on study intervention for immune 
and/or tumor cell profiling that may include immune cell phenotyping, enumerations, 
and/or activation state. Both genome-wide and targeted messenger RNA expression 
profiling and sequencing in tumor, stool, and/or blood may be performed to define gene 
signatures that correlate with treatment outcomes. Epigenetic analyses may also be 
performed as these are important biomarkers for some cancers. Stool samples at baseline 
and on treatment may be evaluated for microbiome profiling to determine if there is any 
association with treatment outcome. 
• Other samples may be used for research, including future research, to develop methods, 
assays, prognostics, and/or companion diagnostics related to immuno-oncology 
treatment, disease process, pathways associated with disease state, and/or mechanisms of 
action of checkpoint inhibitor treatment. 

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8.7.1 
Genetics 
Sample collection, storage, and shipment instructions for planned genetic analysis samples will 
be provided in the Laboratory Manual. Samples should be collected for planned analysis of 
associations between genetic variants in germline/tumor DNA and clinical outcomes to study 
interventions(s). Blood and stool for planned genetic analysis will be collected for DNA as 
described in the SOA (Section 1.3). If a documented law or regulation prohibits (or local 
IRB/IEC does not approve) sample collection for these purposes, then such samples should not 
be collected at the corresponding sites. Additional DNA extracted from planned genetic analysis 
samples will be stored for future biomedical research only if the participant signs the Future 
Biomedical Research consent. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
See Appendix 7 for Information regarding genetic research. 
8.7.2 
Exploratory Biomarkers 
Archival tumor tissue and a fresh tumor biopsy are required if medically feasible at screening for 
exploratory analysis. Additional on-treatment tumor biopsies are required when medically 
feasible: 1) after 2 treatments with study intervention and 2) an optional biopsy at the time of 
disease progression, including from participants who respond and subsequently progress. Core 
needle or incisional tumor biopsy samples are required. Furthermore, every attempt should be 
made for the on-treatment biopsies to be taken from the same lesion site. Fine needle aspiration 
is not allowed. 
Blood will be collected for exploratory biomarkers. Blood may be used for whole blood, 
PBMCs, CTC, plasma, and/or serum preparation, and nucleic acid extraction. Additionally, 
blood samples may be used for profiling of circulating soluble analytes, PK analysis, and 
assessment of ADA for the biologic study intervention components. These blood samples will be 
collected as described in the SOA in Section 1.3. 
Stool samples will be collected for microbiome analysis, which may include microbiome whole 
metagenomic sequencing and/or metabolites as outlined in the SOA in Section 1.3. 
Tissue, blood, and stool sample collection, storage, and shipment instructions are provided in the 
Laboratory Manual. 

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8.7.3 
Sample Collection for Long-term Future Biomedical Research 
8.7.3.1 
Overview of Long-term Future Biomedical Research  
Participants in this clinical trial will be asked to consent to provide biological samples for long-
term future biomedical research. The objective of collecting/retaining specimens for future 
biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of disease and/or their therapeutic treatments. The overarching goal is to use such 
information to understand disease, safety and potential treatments for future participants. Such 
research is for biomarker testing and hypothesis testing to address emergent questions not 
described elsewhere in the protocol (as part of the main trial). 
This research may include genetic and genomic analyses (DNA), gene expression profiling 
(RNA), proteomics, microbiome, metabolomics (serum, plasma, stool) and/or the measurement 
of other analytes, depending on which specimens are consented for future biomedical research. 
The collection and submission of biological samples to be stored for long-term future biomedical 
research must be detailed in the IRB/IEC-approved informed consent form (ICF). Participants 
who do not wish to participate in the future biomedical research may still participate in the study. 
8.7.3.2 
Sample Collection 
The following samples will be collected and stored in accordance with applicable law for long-
term research purposes, including but not limited to, research on biomarkers related to 
immunotherapies, such as anti-PD-1, and diseases such as cancer or inflammatory disorders: 
• Blood, including but not limited to, PBMCs, CTC, and plasma and/or serum 
• DNA 
• RNA 
• Tumor tissue 
• Stool samples 
 
These samples may be sent to one or more laboratories for analysis and/or storage. 
For sampling procedures, storage conditions, and shipment instructions, see the Laboratory 
Manual. 
8.7.3.3 
Withdrawal from Long-term Sample Storage 
Participants have the right to withdraw their consent for the future biomedical research of his 
specimens at any time for any reason and request that their specimens be destroyed. If the 
participant wishes to withdraw consent for this testing, the Investigator must inform the Sponsor 
in writing. Any analyses in progress at the time of request for withdrawal or already performed 

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prior to the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is received. 
In the event that the medical records for the main trial are no longer available (eg, if the 
Investigator is no longer required by regulatory authorities to retain the main trial records) or the 
specimens have been completely de-identified, 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. 
8.7.3.4 
Protection of Data Privacy and Data Generation 
Participant specimens and associated data will be labeled with a unique participant identification 
number. Participant medical information associated with the long-term storage of specimens is 
confidential and may be disclosed to third parties only as permitted by the ICF signed by the 
participant or as permitted or required by law. 
Given the complexity and research nature of the exploratory analyses, data derived from long-
term stored specimens will generally not be provided to study Investigators or participants unless 
required by law. 
Data generated from specimens that are stored long term must be available for inspection upon 
request by representatives of national or local health authorities and Sponsor monitors, 
representatives, and collaborators as appropriate and as described in Section 10.1.11. 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
This section is not applicable. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESIS 
This exploratory study is designed to evaluate multiple clinical hypotheses and mechanistically-
defined combinations to evaluate the safety and efficacy of immunotherapy combination in 
participants with mCRPC who have received prior secondary androgen receptor signaling 
inhibitor therapy (eg, abiraterone, enzalutamide, apalutamide). 
9.2 
SAMPLE SIZE DETERMINATION 
The study is not intended or powered for hypothesis testing. The study is intended to provide 
preliminary estimates of AE rates, response rates, effect sizes and CIs to aid the design of later 
studies. A sample size of approximately 15 participants per immunotherapy combination cohort 
will provide these preliminary estimates while limiting exposure. 

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Table 5 provides 95% exact confidence intervals for the proportion of participants experiencing a 
specific AE for sample sizes of 15 and 30 participants per immunotherapy combination cohort. 
These confidence intervals, along with the ORR rate (described below), provide information 
needed to assess the risk-benefit ratio of the immunotherapy combination for expanding the cohort 
to Stage 2 and for the design of further studies. 
Table 5: 
Confidence Intervals for the True Proportion of Adverse Events 
Observed AE rate 
95% Confidence Interval  
(n = 15) 
95% Confidence Interval  
(n = 30) 
6.7% (1/15 or 2/30) 
(0.2%, 31.9%) 
(0.8%, 22.1%) 
13.3% (2/15 or 4/30) 
(1.7%, 40.5%) 
(3.8%, 30.7%) 
20.0% (3/15 or 6/30) 
(4.3%, 48.1%) 
(7.7%, 38.6%) 
26.7% (4/15 or 8/30) 
(7.8%, 55.1%) 
(12.3%, 45.9%) 
33.3% (5/15 or 10/30) 
(11.8%, 61.6%) 
(17.3%, 52.8%) 
40.0% (6/15 or 12/30) 
(16.3%, 67.7%) 
(22.7%, 59.4%) 
AE = adverse event 
 
A Simon two-stage minimax design (Simon, 1989) will be implemented for each cohort. An 
ORR of at least 25% would provide sufficient evidence of clinical activity to warrant further 
investigation, while an ORR of 10% would not be of interest. In Stage 1, 15 participants will be 
enrolled. If there are 2 or more responses in these 15 participants, 15 additional participants will 
be enrolled in Stage 2 for a total of 30 participants in the cohort. If there are 6 or more responses 
in these 30 participants, then the immunotherapy combination will be considered worthy of 
further investigation. This design yields a type I error rate of 0.07 and 77% power when the null 
hypothesis assumes the ORR is 10% and the alternative hypothesis assumes the ORR is 25%. 
Under the null hypothesis, the probability of terminating the cohort after Stage 1 is 55%. 
9.3 
STATISTICAL ANALYSES 
Each immunotherapy combination cohort will be assessed independently of the other cohorts, 
and the data from each cohort will be analyzed separately to preserve confidentiality of data 
between companies. 
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
provide further details regarding the definition of analysis variables, analysis methodology, and 
handling of missing data. Any combination-specific modifications to the statistical methods, 
including any additional combination-specific endpoints, will be captured in the SAP. The SAP 
will serve as a compliment to the protocol and supersedes it in case of differences. 

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9.3.1 
Efficacy Analyses 
The analyses for clinical activity will be performed on the evaluable population, consisting of all 
participants who receive at least 1 dose of the combination study intervention or any component 
of the combination.  
This study is not intended or powered for hypothesis testing. Due to the exploratory nature of 
this study, no control of type I error will be applied for any of the endpoints. 
9.3.1.1 
Primary Efficacy Endpoint 
There are no primary efficacy objectives or endpoints for this study. 
9.3.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
• ORR: A composite endpoint where response is defined as a participant meeting at least 
one of the following: 
o CTC response: Change from unfavorable (≥ 5 cells/7.5 mL of blood) to favorable 
(≤ 4 cells/7.5 mL of blood). Participants with a baseline CTC value < 5 cells/7.5 
mL of blood will not be evaluated for this criterion. 
o Prostate-specific antigen (PSA) response: Confirmed PSA response is defined as 
≥ 50% reduction in PSA from baseline, with a repeat assessment confirming the 
result at least 3 weeks later. Participants without a PSA value at baseline and at 
least two post-baseline assessments will not be evaluable for this criterion. 
o Confirmed response of CR or partial response (PR) by objective radiographic 
disease assessment using modified RECIST version 1.1 (ie, CR or PR and no 
progression in bone per the PCWG3; Scher et al., 2016). Per RECIST, to be 
assigned a best overall response of CR or PR, changes in tumor measurements 
must be confirmed by repeat assessments that should be performed no less than 4 
weeks after the criteria for response are first met. Participants who received at 
least 1 dose of the combination study intervention or component of the 
combination but do not have RECIST assessment for any reason will be counted 
as not responding. 
• Disease control rate (DCR) at 9 months: Defined as CR, PR, or stable disease (SD) 
for 9 months as best response by PCWG3-modified RECIST 1.1. Participants who 
received at least 1 dose of the study intervention combination or component of the 
combination but do not have RECIST assessment for any reason will be counted as not 
responding. 

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• Radiographic progression-free survival (rPFS): Defined as time from initiation of study 
intervention to the first objective evidence of radiographic progression, or death due to 
any cause (whichever occurs first). Radiographic disease progression includes soft tissue 
disease progression per PCWG3-modified RECIST 1.1 and confirmed progression of 
bone disease per PCWG3 criteria. Participants who continue treatment beyond initial 
disease progression will be considered to have PD at the time of the initial progression 
event. Participants who do not have radiographic progression will be censored at 
initiation of subsequent anti-cancer therapy. 
• OS: Defined as the time from initiation of study invention until death due to any cause. 
• OS rate at 12 months. 
 
Response rates for ORR, DCR, and OS will be estimated within each immunotherapy 
combination cohort and 95% CIs will be estimated using the Clopper-Pearson method. rPFS and 
OS will be estimated using Kaplan-Meier techniques, and the median survival time and 95% CIs 
will be estimated within each immunotherapy combination cohort. If median survival is not 
reached, survival times and 95% CIs will be reported at deciles that are estimable given the 
observed events. 
9.3.1.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints include but are not limited to: 
• Association of tumor and immune biomarkers from tissue, blood, and/or stool with 
clinical outcomes, including ORR, DCR, rPFS, and tolerability. Biomarkers to be studied 
will be chosen based on the immunotherapy combination. 
• Molecular characterization of CTC and evaluation of percent change from baseline. 
• Enumeration of CTC ≥ 1 at baseline with conversion to a measure of zero CTC (CTC0) 
on treatment. 
• Percent change in PSA from baseline at 12 weeks. 
• Maximum change in PSA at any point after study treatment initiation. 
• Time to PSA progression defined as the time from study treatment initiation to the date 
that a ≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline 
value for participants who did not have a decline in PSA) in PSA. The increase must be 
confirmed by a second consecutive assessment conducted at least 3 weeks later. 
• Sparse PK analysis. 

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• Presence of ADA against biologic components of each immunotherapy combination. 
 
9.3.2 
Safety Analyses 
All safety analyses will be performed on the evaluable population, consisting of all participants 
who receive at least 1 dose of the combination study intervention or any component of the 
combination. 
Safety will be assessed through summaries of AEs, laboratory test results (hematology and serum 
chemistry), vital signs, and ECGs. Verbatim descriptions of treatment-emergent AEs (defined in 
Section 10.5.1.4) will be coded, and their incidence will be summarized by immunotherapy 
combination cohort. In addition, separate summaries will be generated for SAEs, deaths, AEs 
leading to study discontinuation, AEs leading to treatment discontinuation, and AEs leading to 
temporary interruption and/or dose reduction. 
9.3.3 
Other Analyses 
The number of participants who were screened, enrolled and treated, enrolled and not treated, 
and completed the study will be presented in summary tables. The reason for discontinuation 
from the study will be listed by participant and summarized in a table. The number of 
participants in each immunotherapy combination cohort and analysis population will be 
summarized. 
Demographic and baseline characteristics of the study population will be summarized overall and 
for each immunotherapy combination cohort. Categorical measures will be summarized using 
frequencies and percentages. Continuous variables will be summarized using means, standard 
deviations, medians, minimums, and maximums. 
9.3.3.1 
Pharmacokinetic Analysis 
Sparse PK analysis may be performed evaluating trough levels for all biologic study intervention 
and maximum observed drug concentration (Cmax) for exploratory biologic study intervention 
(non-PD-1 agents) when possible. 
9.3.3.2 
Biomarker Analysis 
Descriptive statistics will be used to evaluate the exploratory biomarkers. Biomarker exploratory 
analyses will be determined based on study outcomes and further described in a Biomarker 
Analysis Plan.  
9.3.3.3 
Anti-Drug Antibody Analysis 
The number of participants who develop ADA to biologic study intervention and ADA titer may 
be summarized. 

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9.4 
POPULATIONS FOR ANALYSIS 
For purposes of analysis, the following populations are defined as shown in Table 6. 
Table 6: 
Populations for Analysis 
Population 
Description 
Evaluable Population 
All participants who receive at least 1 dose of the combination study 
intervention or any component of the combination  
 
9.5 
INTERIM ANALYSES 
Safety and efficacy will be monitored on a regular basis. Possible adaptations resulting from 
these data reviews include: 
• Modifying or stopping a cohort early based on a safety signal 
• Expanding a cohort to include an additional approximately 15 patients (Stage 2) based on 
acceptable safety data in addition to preliminary signals in clinical activity and/or 
biomarker results 
 
Other possible adaptation to the study design, including the addition of new combination cohorts, 
may be based on a variety of factors, such as emerging biological knowledge of mCRPC 
biomarkers and/or immunotherapy mechanisms, as well as availability of investigational 
therapies. However, it is not anticipated that findings from safety and efficacy monitoring of this 
study will influence these decisions. Findings will not be used to re-estimate the sample size. 
Due to the exploratory nature of this study, effect sizes and CIs will not be adjusted to account 
for ongoing review of data. 
9.5.1 
Interim Safety Monitoring 
To ensure careful review of the accumulating safety data for the PICI0033 platform study, a 
Safety Assessment Committee (SAC) will be established. 
Ongoing safety data review will be conducted by the SAC. The PICI0033 SAC will have a core 
membership made up of genitourinary (GU) oncologists and immuno-oncologists and subject 
matter expert(s) as appropriate for a specific cohort (ie, vaccine expertise). Select Sponsor 
personnel, including the Medical Monitor and representatives from other functions including, but 
not limited to, Biostatistics, Clinical Science, and Drug Safety, will be responsible for producing 
output for review and informing the SAC of any major safety signals in a timely manner. 

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To ensure participants’ safety during the study, the SAC will meet approximately every 3 months 
to assess the totality of safety information in the clinical study. In addition, the SAC or the 
Sponsor may request ad hoc reviews at any time to address potential safety concerns. In the 
event there are a total of 4 or more of the first 15 participants, or 8 or more of 30 participants if a 
cohort is expanded, in a single cohort that meet cohort-specific toxicity criteria, an ad hoc SAC 
meeting will be held. If 1 death in any cohort occurs that is possibly related to the study drugs, 
the specific cohort will be placed in temporary suspension of enrollment until the information 
can be assessed by the Sponsor and in consultation with the SAC. 
Safety monitoring will include unblinded evaluation of all AEs, SAEs, relevant protocol 
deviations, and laboratory data. If the SAC deems a benefit-risk assessment necessary, the SAC 
may also review efficacy data. The SAC may recommend terminating a combination cohort or 
suspending enrollment for safety reasons. 
Roles and responsibilities of the SAC will be detailed in a separate charter. 
9.5.2 
Cohort Expansion Rules 
A Simon two-stage minimax design (Simon, 1989) will be implemented for each cohort. In Stage 
1, 15 participants will be enrolled. If there are 2 or more responses in these 15 participants, 15 
additional participants will be enrolled in Stage 2 for a total of 30 participants in the cohort. For 
the purposes of cohort expansion, ORR will be used to determine response (ie, CTC response, 
PSA response, or confirmed response of CR or PR). 
In addition to efficacy criteria stated above, safety data will also be assessed when determining 
whether to expand a cohort. If there are ≥ 6 participants meeting cohort-specific toxicity criteria 
requiring permanent treatment discontinuation, an ad hoc SAC meeting will be held to further 
review all safety data and provide input on assessing the benefit-risk profile. The SAC will 
provide a recommendation in regard to expansion to Stage 2, continuation or discontinuation of 
the cohort. This ad hoc review will be in addition to the ongoing safety monitoring performed by 
the SAC, who may recommend terminating a combination cohort at any time for safety reasons.  
The threshold of 6 participants was chosen because this translates to a posterior probability of 
0.69 that the true toxicity rate is >30%, assuming 15 participants are enrolled per cohort and a 
minimally informative beta (0.5, 2.5) prior. 
If the cohort has an acceptable safety profile but has not demonstrated at least 2 responses, no 
additional participants will be enrolled into the cohort. However, this decision may be revisited if 
follow-up translational analysis or emerging external data identifies a subset of participants most 
likely to derive benefit from the combination therapy that was underrepresented in the cohort. 
Under this scenario, any modifications to the study design of the combination, including 

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justification for participant selection or enrichment, will be detailed in an amendment to the 
appropriate cohort appendix. 
 

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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1: REGULATORY, ETHICAL AND STUDY 
OVERSIGHT CONSIDERATIONS 
10.1.1 
Compliance with Laws and Regulations 
This study will be conducted in accordance with the protocol and with the following: 
• Applicable International Council for Harmonisation (ICH) guidelines, including E6(R2) 
for Good Clinical Practice (GCP) and E2A for Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable laws and regulations. 
 
Studies conducted in the US or under a US Investigational New Drug (IND) application will 
comply with US FDA regulations and applicable local, state, and federal laws.  
10.1.2 
Institutional Review Board or Independent Ethics Committee 
The protocol, protocol amendments, ICF(s), IB, any information to be given to the participant, 
and relevant supporting information must be submitted to the IRB/IEC and reviewed and 
approved by the IRB/IEC before the study is initiated. In addition, any participant recruitment 
materials (eg, advertisements) must be approved by the IRB/IEC. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants or changes that involve logistical or administrative aspects only (eg, 
change in Medical Monitor or contact information).  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Promptly documenting and reporting any deviations that might have an impact on 
participant safety and data integrity to the Sponsor and to the IRB/IEC in accordance with 
established requirements, policies and procedures 

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• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations. 
 
10.1.3 
Financial Disclosure 
Investigators and Sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate health authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study (see definition of end of study in Section 4.5). 
10.1.4 
Informed Consent 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his legally authorized representative and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
If applicable, the ICF will contain separate sections for any optional procedures. The Investigator 
or authorized designee will explain to each participant the objectives, methods, and potential 
risks associated with each optional procedure. Participants will be told that they are free to refuse 
to participate and may withdraw their consent at any time for any reason. A separate, specific 
signature will be required to document a participant’s agreement to participate in optional 
procedures. Participants who decline to participate will not provide a separate signature. 
Participants must be re-consented to the most current version of the ICF(s) (or to a significant 
new information/findings addendum in accordance with applicable laws and IRB/IEC policy) 
during their participation in the study. The medical record should document the re-consent 
process and that written informed consent was obtained using the updated/revised ICF for 
continued participation in the study. 
A copy of the signed and dated ICF(s) must be provided to the participant or to the participant’s 
legally authorized representative. All signed and dated ICFs must remain in the participant’s 

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study file or in the site study file and must be available for verification by study monitors at any 
time. 
The final revised IRB/IEC-approved ICFs must be provided to the Sponsor for the purpose of 
health authority submission. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date and provided the ICF has not been updated 
during that time. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a participant's agreement to 
allow any remaining specimens to be used for exploratory research. Participants who decline to 
participate in this optional research will not provide this separate signature. 
10.1.5 
Data Protection 
The Sponsor maintains confidentiality standards by assigning a unique participant identification 
number to each participant enrolled in the study. This means that participant names are not 
included in data sets that are transmitted to any Sponsor location. 
Participant medical information obtained by this study is confidential and may be disclosed to 
third parties only as permitted by the ICF (or separate authorization for use and disclosure of 
personal health information) signed by the participant or as permitted or required by law. 
Medical information may be given to a participant’s personal physician or other appropriate 
medical personnel responsible for the participant’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, Sponsor monitors, representatives and collaborators, and the 
IRB/IEC for each study site, as appropriate. 
10.1.6 
Dissemination of Clinical Study Data 
The results of this study may be reported to the public, in the form of a publication or 
presentation at scientific congresses, before completion of the study. 
10.1.7 
Administrative Structure 
This trial will be sponsored and managed by the Parker Institute for Cancer Immunotherapy. The 
Sponsor will provide clinical operations management, data management, medical monitoring, 
and safety oversight. 

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Central facilities will be used for certain study assessments throughout the study (eg, specified 
laboratory tests, PK analyses, biomarker analyses), as specified in Section 8.2.5, Section 8.5, and 
Section 8.7, respectively. Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 
10.1.8 
Data Quality Assurance 
All participant data relating to the study will be collected via the electronic data collection (EDC) 
on an eCRF unless transmitted to the Sponsor or designee electronically (eg, central laboratory 
data, biomarker and other biological sample data). Sites will be responsible for data entry into 
the EDC system and will receive training for appropriate eCRF completion. The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically signing and 
dating the eCRF. 
The Investigator must maintain accurate documentation (source data, see Section 10.1.9) that 
supports the information entered on the eCRF. The Investigator must permit study-related 
monitoring, audits, IRB/IEC review, and regulatory agency inspections and provide direct access 
to source data documents. 
The Sponsor is responsible for the data management of this study, including quality checking of 
the data. Study monitors will perform ongoing source data verification to confirm that data 
entered on the eCRF 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. 
At the end of the study, the Investigator will receive participant data for his/her site in a readable 
format on a compact disc (or other readable digital format) that must be kept with the study 
records. Acknowledgement of receipt of the compact disc is required. 
10.1.9 
Source Documentation 
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 entered 
on 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. 
Source documents (paper or electronic) are those in which participant data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, clinical outcomes assessment (COA)/patient-
reported outcomes (PRO), evaluation checklists, pharmacy dispensing records, recorded data 

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from automated instruments, copies of transcriptions that are certified after verification as being 
accurate and complete, microfiche, photographic negatives, microfilm or magnetic media, 
X-rays, participant files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
When clinical observations are entered directly into a study site’s computerized medical record 
system (ie, in lieu of original hardcopy records), the electronic record can serve as the source 
document if the system has been validated in accordance with health authority requirements 
pertaining to computerized systems used in clinical research. An acceptable computerized data 
collection system allows preservation of the original entry of data. If original data are modified, 
the system should maintain a viewable audit trail that shows the original data as well as the 
reason for the change, name of the person making the change, and date of the change. 
Source documents that are required to verify the validity and completeness of data entered on the 
eCRFs must not be obliterated or destroyed and must be retained as described in Section 10.1.12. 
10.1.10 
Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Reasons for terminating the study may 
include, but are not limited to, the following: 
• Discontinuation of further study intervention development 
• The incidence or severity of AEs in this or other studies indicate the potential hazard to 
participants 
• Participant enrollment is unsatisfactory 
 
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to, the following: 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
• No study activity (ie, all participants have completed the study and all obligations have 
been fulfilled) 
 

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10.1.11 
Site Inspections 
Site visits will be conducted by the Sponsor or an authorized representative for inspection of 
study data, participants’ medical records, and eCRFs. The Investigator will permit national and 
local health authorities; Sponsor monitors, representatives and collaborators; and the IRBs/IECs 
to inspect facilities and records relevant to this study. 
10.1.12 
Retention of Records 
Records and documents pertaining to the conduct of this study and distribution of the 
investigational medicinal product, including signed eCRFs, electronic or paper COA/PRO data 
(if applicable), signed ICFs, laboratory test results, and medication inventory records, must be 
retained by the Investigator for the maximum period required by applicable regulations of 
relevant national or local health authorities. No records may be disposed of without the written 
approval of the Sponsor. The Sponsor will notify the Investigator when the records are no longer 
needed. Following notification from the Sponsor, the documents may be destroyed, subject to 
local regulations.  
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
10.1.13 
Publication Policy and Protection of Trade Secrets 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing information on 
the trial to healthcare professionals and to the public, both at scientific congresses and in peer-
reviewed journals. The Sponsor will comply with all requirements for publication of study 
results. 
The Investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may not yet 
be available to the Investigator. 
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 trials only in their entirety and not as individual center data. In this case, a 
Coordinating Investigator will be designated in accordance with the Parker Institute for Cancer 
Immunotherapy publication policy. Authorship will be based on overall scientific contribution 
and participant enrollment. 

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10.2 
APPENDIX 2: EASTERN COOPERATIVE ONCOLOGY 
GROUP (ECOG) PERFORMANCE STATUS 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair 
5 
Dead 
Source: Oken et al., 1982 
 

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10.3 
APPENDIX 3: RECIST CRITERIA (VERSION 1.1) WITH 
MODIFICATIONS AS RECOMMENDED BY PCWG3 
Tumor response will be assessed according to RECIST v1.1 (Eisenhauer et al., 2009; 
Section 10.3.1 and Section 10.3.2), with modifications as recommended by PCWG3 (Scher et al., 
2016; Section 10.3.3), as described below. 
10.3.1 
Measurability of Tumor at Baseline 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable as 
follows: 
• Measurable 
Tumor lesions: Must be accurately measured in ≥ 1 dimension (longest diameter in the 
plane of measurement to be recorded) with a minimum size of: 
o 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
o 10 mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable) 
o 20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). 
• Nonmeasurable 
o All other lesions (or disease sites), including small lesions (longest diameter < 10 mm 
or pathological lymph nodes with ≥ 10 to < 15 mm short axis) 
o Lesions considered truly nonmeasurable include the following: leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, and abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques 
 

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10.3.2 
Tumor Response Evaluation 
10.3.2.1 
Baseline Documentation of Target and Nontarget Lesions 
• Target lesions 
o When > 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions total (and a maximum of 2 lesions per organ) representative of all involved 
organs should be identified as target lesions 
o It may be the case that, on occasion, the largest lesion that can be measured 
reproducibly should be selected 
• Nontarget lesions 
o All other lesions (or disease sites), including pathological lymph nodes, should be 
identified as nontarget lesions 
o It is possible to record multiple nontarget lesions involving the same organ as a single 
item (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’) 
10.3.2.2 
Evaluation of Target Lesions 
Target lesions will be evaluated and response recorded as defined in Appendix Table 1. 
Appendix Table 1: 
Response Based on Evaluation of Target Lesions at Each Assessment 
Complete response 
Disappearance of all target lesions; if a pathologic lymph node, 
reduction in the shortest axis to < 10 mma 
Partial responseb 
≥ 30% decrease in the sum of the diameters of target lesions relative 
to the baseline sum diametersc 
Stable diseaseb,d 
Neither a sufficient reduction to qualify as a partial response nor a 
sufficient increase to qualify as progressionc 
Progressive diseaseb 
≥ 20% increase in the sum diameters relative to the smallest sum 
diameters recorded (including the baseline sum diameters) in 
conjunction with an increase of at least 5 mm in that smallest sum 
diameters, or the appearance of 1 or more new lesionsc,e 
a For each pathologic lymph node considered a target lesion, the node must have a short axis measuring < 10 mm to 
be considered as a complete response. In such cases, the sum diameters may not be zero (as a normal lymph node 
can have a short axis of < 10 mm). 
b For each pathologic lymph node considered a target lesion, the measurement of the short axis of the node is to be 
included in the sum diameters when determining partial response, stable disease, and progression. 
c In this study, the “baseline sum diameters” is calculated based on the lesion measurements obtained at screening. 
d Duration of stable disease is measured from the date of the first dose of Study treatment until criteria for 
progressive disease are met based on the smallest sum diameters recorded (including the baseline sum diameters). 
e The finding of a new lesion should be unequivocal and not possibly attributable to a difference in imaging 
modality or scanning technique. Post-baseline, fluorodeoxyglucose positron emission tomography (FDG-PET) 
may be useful in assessing new lesions apparent on CT scan. 

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10.3.2.3 
Evaluation of Nontarget Lesions 
Nontarget lesions will be evaluated and response recorded as defined in Appendix Table 2. 
Appendix Table 2: 
Response Based on Evaluation of Nontarget Lesions at Each 
Assessment 
Complete response 
Disappearance of all non-target lesions; all lymph nodes must be 
nonpathologic in size (ie, < 10 mm on the short axis) 
Not complete response nor 
progressive disease 
Persistence of 1 or more non-target lesions 
Progressive disease 
Unequivocal progressiona of any existing non-target lesion or the 
appearance of 1 or more new lesionsb 
a The participant should stop study intervention, even in the presence of a partial response or stable disease, based 
on assessment of target lesions. 
b The finding of a new lesion should be unequivocal and not possibly attributable to a difference in imaging 
modality or scanning technique. Post-baseline, fluorodeoxyglucose positron emission tomography (FDG-PET) 
may be useful in assessing new lesions apparent on CT scan. 
 
10.3.2.4 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (eg, some ‘new’ bone 
lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the participant’s baseline lesions show PR or CR. For example, necrosis of a liver lesion 
may be reported on a CT scan as report as a ‘new’ cystic lesion, which it is not. 
10.3.2.5 
Evaluation of Overall Response 
Overall response based on the evaluation of target and nontarget lesions will be determined as 
shown in Appendix Table 3. 
Appendix Table 3: 
Evaluation of Overall Response at Each Assessment 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response 
No 
Complete response 
No target lesiona 
Complete response 
No 
Complete response 
Complete response 
Not evaluableb 
No 
Partial response 
Complete response 
Not complete response/ 
non-progressive disease 
No 
Partial response 

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Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
Partial response 
Non-progressive disease and 
not evaluableb 
No 
Partial response 
Stable disease 
Non-progressive disease and 
not evaluableb 
No 
Stable diseasec 
Not all evaluated 
Non-progressive disease 
No 
Not evaluable 
No target lesiona 
Not all evaluated 
No 
Not evaluable 
No target lesiona 
Non-complete response/ 
non-progressive disease 
No 
Non-complete response/ 
non-progressive disease 
Progressive disease 
Any 
Yes or no 
Progressive disease 
Any 
Progressive disease 
Yes or no 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
No target lesiona 
Unequivocal progressive disease 
Yes or No 
Progressive disease 
No target lesiona 
Any 
Yes 
Progressive disease 
a Defined as no target lesions at baseline. 
b Not evaluable is defined as either when no or only a subset of lesion measurements are made at an assessment. 
c The minimum duration on-study required for an overall assessment of stable disease is 49 days. 
 
10.3.3 
Modifications for mCRPC as Recommended by PCWG3 
In 2016, the PCWG3 (Scher et al., 2016) updated the recommendations of the Prostate Cancer 
Working Group 2 (PCWG2; Scher et al., 2008). The key new recommendations related to 
disease assessment, including the following, which are described in more detail in Section 
10.3.3.1 and Section 10.3.3.2: 
• emphasizing the importance of serial biologic profiling of the disease using minimally 
invasive blood-based assays of tumor material, imaging, or biopsy of a metastatic tumor 
site to identify and target mechanisms of primary or adaptive resistance and to better 
enable treatment selection to be based on disease biology; 
• including clinically relevant time-to-event end points, such as symptomatic skeletal 
events (SSEs); 
• with increased recognition of disease heterogeneity and emerging resistance, focusing 
more on determining when a treatment should be discontinued when the patient is NLCB 
rather than strictly at the first evidence of progression. 
 

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10.3.3.1 
PCWG3 Recommendations with Regard to Baseline Disease 
Assessments 
A summary of major changes in PCWG3 recommendations compared with PCWG2 with regard 
to baseline disease assessments follows: 
• Expands baseline assessments to include tumor histology; the timing, duration, and 
response (if available) for all prior systemic treatments; a standardized assessment of 
blood-based, PRO-based, and imaging-based biomarkers; and the molecular 
characterization of the tumor (detailed in Appendix Table 4). 
• Emphasizes molecular/biologic subtypes of castration-resistant prostate cancer in 
addition to the 5 clinical subtypes (defined by extent and location of metastases) 
• Defines the type of progression at trial entry as PSA-only progression, radiographic 
progression by site of disease spread, or both; for radiographic progression, records 
whether progression was caused by growth of existing lesions, appearance of new 
lesions, or both 
 
Appendix Table 4: 
Criteria for Progression at Trial Entry by Disease Manifestation 
Variable 
PCWG3 Recommendation 
Blood-based 
PSA 
Obtain sequence of rising values at a minimum of 1-week intervals 
1.0 ng/mL minimal starting value 
(1.0 ng/mL is the minimal starting value if confirmed rise is only indication of 
progression unless pure small-cell carcinoma) 
Estimate pretherapy PSA doubling time if at least 3 values available ≥ 4 weeks apart 
Imaging 
Nodes 
Nodal progression sufficient for trial entry independent of PSA 
Measurable lesions not required for entry 
Modified RECIST 1.1 criteria, separate pelvic and disease, up to five nodal lesions total 
recorded 
Previously normal (< 1.0-cm) lymph nodes must have grown by ≥ 5 mm in the short 
axis from baseline or nadir and be ≥ 1.0 cm in the short axis to be considered to have 
progressed 
If the node progresses to ≥ 1.5 cm in the short axis, it is measurable; nodes that have 
progressed to 1.0 to less than 1.5 cm are pathologic, subject to clinical discretion, and 
nonmeasurable 
For existing pathologic adenopathy, progression is defined per RECIST 1.1 
Record presence of nodal and/or visceral disease separately 
Nodal sites: 
Locoregional: pelvic only 
Extrapelvic: retroperitoneal, mediastinal, thoracic, or other 

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Variable 
PCWG3 Recommendation 
Viscera 
Visceral progression sufficient for trial entry independent of PSA; recorded separately 
by site of spread (lung, liver, adrenal, CNS); up to 5 lesions per site of spread 
recorded 
Measurable lesions not required for entry 
Use RECIST to record visceral lesions as target or nontarget 
Visceral sites: lung, liver, adrenal, CNS 
Prostate/prostate bed 
(primary site) 
Record prior treatment of primary tumor 
Perform directed pelvic imaging (CT, MRI, PET/CT, endorectal MRI, transrectal 
ultrasound) to document presence or absence of disease 
Bone 
Two new lesions 
Confirm ambiguous results by other imaging modalities (eg, CT or MRI); only 
positivity on the bone scan defines metastatic disease to bone 
Other sites of disease 
Patients with treated epidural lesions and no other epidural progression are eligible 
Type of progression at trial entry 
 
Report separately: 
PSA only 
Bone only ± nodal disease 
Nodal disease only (no bone disease present) 
Visceral (lung, liver, adrenal, CNS) disease (± other sites) 
Record new lesions and site of new lesions vs growth of pre-existing lesions, or both 
Other markers 
Patient-reported 
outcomes 
For pain palliation analyses, presence of clinically meaningful pain at baseline (eg, ≥ 4 
on a 10-point pain intensity scale) is a prerequisite; for pain progression analyses, 
patients may have any level of pain at baseline, including no pain 
Source: Scher et al., 2016  
CNS = central nervous system; CT = computed tomography; MRI = magnetic resonance imaging; 
PCWG3 = Prostate Cancer Clinical Trials Working Group 3; PET = positron emission tomography; PSA = prostate-
specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; vs = versus 
 
10.3.3.2 
PCWG3 Recommendations with Regard to Measuring Outcomes 
and Reporting 
PCWG3 reaffirmed the PCWG2 recommendation for the use of the following endpoints to assess 
antitumor effects, and suggested the outcome measures described in Appendix Table 5 are 
differentiated according to these endpoints, where applicable: 
• Control/relieve/eliminate endpoints for therapies that are anticipated to kill tumor cells, 
particularly in early clinical development 
• Delay/prevent endpoints for therapies not expected to kill tumor cells 
 
A summary of major changes in PCWG3 recommendations compared with PCWG2 with regard 
to measuring outcomes and reporting follows: 

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Blood-based and Molecular Measures 
• When there are progressing lesions, recommends rebiopsy of the progressing metastatic 
site for histology and biomarker assessment 
• Suggests that PSA outcomes should be interpreted within the context of a drug’s 
mechanism of action, and the anticipated timing of a potential favorable/unfavorable 
effect on PSA should be considered 
• Includes suggestions on how to define and report outcomes related to CTC enumeration 
(using CellSearch platform) 
 
Patient-reported Outcomes 
• Recognizes the importance of the patient perspective in prostate cancer clinical trials and 
the need to further optimize the assessment, collection, analysis, and presentation of PRO 
data 
• Recommends measuring disease-related symptoms including pain intensity and 
interference, and physical functioning, using validated instruments 
• Recommends collecting patient-reported AEs using the National Cancer Institute’s 
(NCI’s) PRO- Common Terminology Criteria for Adverse Events (CTCAE) 
 
Imaging and Clinical Measures 
• Reconsiders the mixed response designation, which may be a manifestation of disease 
heterogeneity 
• Advises recording whether disease progression represents growth of pre-existing lesions, 
development of new lesions, or both, and separately recording whether progression is 
occurring in a single organ or disease site versus (vs) multiple sites 
• Suggests that the first post-treatment bone scan be used as the baseline scan with which 
all future bone scans are compared; also emphasizes the notion of response in bone, 
caused by the advent of novel bone-targeting agents 
• Advises recording the location of nodal disease (pelvic vs extrapelvic) and visceral 
disease (lung/liver/adrenal/central nervous system [CNS]) separately, because these sites 
have separate prognostic implications 
• Also advises monitoring up to 5 individual lesions per site of spread (eg, nodes, lung, 
liver as separate sites) to address disease heterogeneity 

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• Proposes new criteria to define the first occurrence of metastatic disease in men with 
nonmetastatic CRPC (nmCRPC) at enrollment 
• Highlights and defines the bone-related outcomes, skeletal-related events (SREs) and 
SSEs, but suggests focusing on SSEs, which represent a more direct clinical benefit to 
patients 
• Introduces the concept of treatment beyond progression where clinical benefit by one or 
more disease manifestations is being observed, thus defining an objective of NLCB 
 
Appendix Table 5: 
Suggested Outcome Measures for Clinical Trials in Metastatic 
Prostate Cancer: Report by Disease Manifestation 
Variable 
PCWG3 Recommendation 
Histology 
 
Encourage rebiopsy of metastatic sites or local recurrence at progression to evaluate for 
histologic (ie, neuroendocrine/ small cell) transformation; in the context of clinical 
trials, encourage rebiopsy for biomarker assessment 
Blood-based markers 
PSA 
Recognize that a favorable effect on PSA may be delayed for ≥ 2 weeks, even for a 
cytotoxic drug 
Monitor PSA by cycle but plan to continue through early rises for a minimum of 8-9 or 
12 weeks (depending on trial design) unless other evidence of progression 
Ignore early rises (before 12 weeks) in determining PSA response 
For control/relieve/eliminate end points: 
Record the percent change from baseline (rise or fall) at 12 weeks, and separately, the 
maximal change (rise or fall) at any time using a waterfall plot 
Separately report the proportion of patients who have undergone radical 
prostatectomy and achieved a nadir less than 0.2 ng/mL v primary radiation 
therapy–treated patients who achieved a nadir less than 0.5 ng/mL 
Describe absolute changes in PSA over time from baseline to best response 
For delay/prevent end points (progression): 
After decline from baseline: record time from start of therapy to first PSA increase 
that is ≥ 25% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second 
value ≥ 3 weeks later (ie, a confirmed rising trend); the requirement for an increase 
of 5 ng/mL was decreased to 2 ng/mL, and the requirement for a 50% increase was 
reduced to 25% 
Recording the duration of PSA decline of little value 
No decline from baseline: PSA progression ≥ 25% increase and ≥ 2 ng/mL increase 
from baseline beyond 12 weeks; relate to mechanism of drug and anticipated timing 
of potential favorable/unfavorable effects on PSA, if present 
CTC 
Enumerate at the start of treatment: Record as favorable (≤ 4 cells/7.5 mL of blood) or 
unfavorable (≥ 5 cells/7.5 mL) 
If unfavorable, monitor for changes after treatment 
For control/relieve/eliminate end points: 
Report as change from unfavorable (≥ 5 cells/7.5 mL of blood) to favorable (≤ 4 
cells/7.5 mL) and separately, the percent change from baseline using a waterfall plot 

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Variable 
PCWG3 Recommendation 
For delay/prevent end points: no validated definition exists (however, rising CTC 
counts are associated with a poor prognosis) 
LDH, total alkaline 
phosphatase, bone-
specific alkaline 
phosphatase, urine 
N-telopeptide, 
hemoglobin, NLR 
Descriptively report changes over time, may include the proportion showing 
normalization of a given biomarker and/or waterfall plots of percent change from 
baseline in a given biomarker 
Report institutional normal ranges to determine normalization of a given biomarker 
Imaging biomarkers: nodal and visceral 
For control/relieve/eliminate endpoints 
General 
Record up to 5 lesions per site of disease 
Use RECIST 1.1 with caveats: 
Record changes in size using waterfall plot 
Confirm favorable change with second scan 
Record complete elimination of disease at any site separately 
Nodes 
Only report changes in lymph nodes that were ≥ 1.5 cm in the short axis 
Record changes in pelvic (regional) nodes vs extrapelvic (distant/metastatic) nodes 
separately 
Visceral 
Use RECIST 1.1 with caveats: 
Record changes in liver, lung, adrenal, and CNS separately 
Only report changes in lesions ≥ 1.0 cm in the longest dimension 
For delay/prevent endpoints 
Nodal and visceral 
Record changes in nodal and visceral (lung, liver, adrenal, and CNS) disease separately 
Use RECIST 1.1 but clearly record type of progression (growth of existing lesions vs 
development of new lesions) separately by site 
The recommendations apply to both nmCRPC and mCRPC 
Record up to 5 lesions per site of spread 
Report the proportion who have not progressed at fixed time points (6 or 12 months) 
Note that for some treatments, a lesion may increase in size before it decreases 
Nodal 
Previously normal (< 1.0-cm) lymph nodes must have grown by ≥ 5 mm in the short 
axis from baseline or nadir and be ≥ 1.0 cm in the short axis to be considered to have 
progressed 
Nodes that have progressed to 1.0 to less than 1.5 cm are pathologic, subject to clinical 
discretion, and nonmeasurable 
For existing pathologic adenopathy (≥ 1.5 cm), progression is defined per RECIST 1.1 
Imaging biomarkers: bone 
Metastatic 
For control/relieve/eliminate endpoints: 
Record changes as resolved, improved, or stable (no new lesions) or worse (new 
lesions) 
Changes in intensity of uptake alone do not constitute progression or regression 
No new lesions: continue therapy in absence of other signs of progression 
New lesions (See Progression below) 
For delay/prevent endpoints (progression): 
Progression: 
Exclude pseudoprogression in the absence of symptoms or other signs of 
progression 
At least 2 new lesions on first post-treatment scan, with at least 2 additional lesions 
on the next scan (2+2 rule) 

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Variable 
PCWG3 Recommendation 
If at least 2 additional new lesions are seen on the next (confirmatory) scan, the date 
of progression is the date of the first post-treatment scan, when the first 2 new 
lesions were documented 
For scans after the first post-treatment scan, at least 2 new lesions relative to the first 
post-treatment scan confirmed on a subsequent scan 
Date of progression is the date of the scan that first documents the second lesion 
Changes in intensity of uptake alone do not constitute either progression or 
regression 
Report the proportion of patients who have not progressed at fixed time intervals 
(6 and 12 months) 
nmCRPC 
Nonmetastatic to metastatic progression: 
Any new unequivocal bone lesion, except if that lesion appears in the first post-
treatment scan; in that case, document the event, continue treatment until 2 additional 
new lesions appear, and record both events 
Patient-reported outcomes 
 
Pain palliation assessment requires a patient population with clinically meaningful pain 
at baseline (eg, ≥ 4 on a 10-point pain intensity scale) and response defined as a 
clinically meaningful score improvement at a subsequent time point (eg, a 30% 
relative or 2-point absolute improvement from baseline at 12 weeks, confirmed at 
least 2 weeks later, without an overall increase in opiate use) 
For control/relieve/eliminate endpoints: 
Document pain and analgesia at entry with a lead-in period and measure repeatedly at 
3- to 4-week intervals; serial (eg, daily x 7 days) assessments at each time point can 
improve the stability of values 
Perform serial assessments of global changes in HRQoL, urinary or bowel 
compromise, pain management, additional anticancer therapy; principles may be 
extended for any PRO for which a clinically meaningful baseline PRO score has 
been determined together with a responder definition that is based on a sustained 
clinically meaningful score improvement 
Ignore early changes (≤ 12 weeks) in pain or HRQoL in absence of compelling 
evidence of disease progression 
For delay/prevent endpoints: 
Confirm response or progression of pain or HRQoL end points ≥ 3 weeks later; 
patients with any level of baseline pain, including no pain, are eligible to be 
evaluated for prevent/delay end points; those without pain are followed for 
development of pain, whereas those with baseline pain are followed for progression 
(eg, a 2-point increase without an overall decrease in opiate use) 
Pain assessment should be administered at treatment discontinuation and once again if 
feasible (eg, 2 to 4 weeks later) 
Time to deterioration of physical function and/or HRQoL scores should also be 
included, with a priori thresholds defining clinically meaningful deterioration 
score changes that are based on prior published data for the selected questionnaire 
Source: Scher et al., 2016  
CNS = central nervous system; CTC = circulating tumor cell; HRQoL = health-related quality of life; LDH = lactate 
dehydrogenase; mCRPC = metastatic castration-resistant prostate cancer; NLR = neutrophil/lymphocyte ratio; 
nmCRPC = nonmetastatic castration-resistant prostate cancer; PCWG3 = Prostate Cancer Clinical Trials Working 
Group 3; PSA = prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumors; vs = versus 
 

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10.4 
APPENDIX 4: CLINICAL LABORATORY TESTS 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in the 
cohort appendix for each respective combination. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 

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10.5 
APPENDIX 5: ADVERSE EVENTS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING 
10.5.1 
Definitions 
10.5.1.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a participant, temporally associated with the 
use of study intervention, whether or not considered related to the study intervention. 
• 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 intervention. 
 
Events Meeting the AE Definition  
• Any abnormality or deterioration in a 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. 
• A new condition detected or diagnosed after study intervention 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 
intervention or a concomitant medication.  
• Serious events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study procedures (eg, screening invasive procedures, such as 
biopsies, discontinuation of non-study medications that may be required by protocol such 
as a prohibited medication). 
• 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 
8.3.6 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. 
 
10.5.1.2 
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 AE that suggests a significant hazard, contraindication, side 
effect, or 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 
In general, hospitalization signifies that the participant has been detained at the hospital or 
emergency ward for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for 
continued observation. 
Note: Hospitalizations for the following reasons are not considered SAEs in this study: 
• a visit to the emergency room or other hospital department for < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
• elective surgery planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy) 

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• medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases 
• admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
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. 
e. 
Is a congenital anomaly/birth defect 
In offspring of a participant exposed to the study intervention for timing as determined for 
study intervention based on product half-life. Any spontaneous abortion should be reported in 
the same fashion (as the Sponsor considers spontaneous abortions to be medically significant). 
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. 
 
10.5.1.3 
Definition of Unexpected AE 
Unexpected AE Definition 
• Any AE, the specificity or severity of which is not consistent with the current IB. Expected 
means that the event has previously been observed with the study intervention and is 
identified and/or described in the current IB. It does not mean that the event is expected 
with the underlying disease(s), co-morbidities or concomitant medications. 
 

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10.5.1.4 
Definition of Treatment-emergent AE 
Treatment-emergent AE Definition 
• Any unfavorable and unintended diagnosis, symptom, sign (including an abnormal 
laboratory finding that is considered to be clinically significant), syndrome or disease that 
either occurs during the study, having been absent at baseline, or, if present at baseline, 
appears to have worsened in severity or frequency, whether or not the event is considered 
related to the study intervention. 
 
10.5.2 
Additional Events Reported in the Same Manner as an SAE 
Additional Events Reported in the Same Manner as a SAE 
• In addition to the SAE criteria in Section 10.5.1.2, AEs meeting any 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. 
o A new cancer (not the indicated condition of the study) 
o An overdose or is an associated event that meets safety criterion with an 
overdose (as specified in Section 8.4) 
o Protocol-specified AEs, including AESIs (as applicable and as defined in the 
cohort appendix for each respective combination) 
o Pregnancy (as specified in Section 8.3.5) 
 

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10.5.3 
Recording AEs and SAEs 
AE and SAE Recording 
• When an AE/AESI/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. Only a single AE term should be recorded for the event. 
• The Investigator will record all relevant AE/AESI/SAE information on the eCRF. 
• 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 Adverse Event eCRF/Serious Adverse 
Event Report Form (SAERF). 
• 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 redacted 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.  
 
Assessment of Severity 
• The terms ‘severe’ and ‘serious’ are not synonymous. 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. Severity (intensity) and seriousness need to be 
independently assessed for each AE recorded on the eCRF. 
• The Investigator will assess the intensity for each AE, including AESI, and SAE (and other 
reportable safety events) according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 5.0, which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
The following grading will be used for assessing intensity for AEs not specifically listed in 
the NCI CTCAE: 
o Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
o Grade 2: Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living. 
o Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
o Grade 4: Life threatening consequences; urgent intervention indicated. 

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o Grade 5: Death related to AE. 
• Any AE that changes CTCAE grade over the course of a given episode (ie, persistent AE) 
will have each change of grade recorded on the Adverse Event eCRF. 
 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/AESI/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use their clinical judgment, knowledge of the participant, the 
circumstances surrounding the event, and an evaluation of any potential alternative causes 
to determine the relationship. 
• The following guidance will be considered and investigated: 
o Temporal relationship of the event onset to study intervention administration 
o Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study intervention, or reintroduction of study intervention (as 
applicable) 
o Known association of the event with the study intervention or with similar 
treatments 
o Known association of the event with the disease under study 
o Presence of risk factors in the participant or use of concomitant medications 
known to increase the occurrence of the event 
o Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/AESI/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/AESI/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. 

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• For studies in which multiple agents are administered as part of a combination regimen, 
the Investigator may attribute each AE 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 are sufficient data to 
support full attribution of the AE to the single agent. 
Causality for this protocol should be assessed as follows: 
• Unrelated: This category applies to those AEs that are clearly and incontrovertibly due to 
extraneous causes (disease, environment, etc.). 
Note: If an AE is assessed as unrelated to the study intervention(s), there must be an 
alternative etiology in the Investigator’s assessment for that event documented in the 
participant’s medical records. 
• Unlikely Related: This category applies to those AEs that are judged to be unrelated to the 
study intervention(s), but for which no extraneous cause may be found. An AE may be 
considered unlikely to be related to study intervention(s) if or when it meets 2 of the 
following criteria: 
o it does not follow a reasonable temporal sequence from administration of the 
study intervention(s); 
o it could readily have been produced by the participant’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
participant; 
o it does not follow a known pattern of response to the study intervention(s); or 
o it does not reappear or worsen when the study intervention(s) is 
re-administered. 
• Possibly Related: This category applies to those AEs for which a connection with the 
study intervention administration appears unlikely but cannot be ruled out with certainty. 
An AE may be considered possibly related if or when it meets 2 of the following criteria: 
o it follows a reasonable temporal sequence from administration of the study 
intervention(s); 
o it could not readily have been produced by the participant’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
participant; or 
o it follows a known pattern of response to the study intervention(s). 
• Probably Related: This category applies to those AEs that the Investigator feels with a 
high degree of certainty are related to the study intervention(s). An AE may be considered 
probably related if or when it meets 3 of the following criteria: 
o it follows a reasonable temporal sequence from administration of the study 
intervention(s); 

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o it could not be reasonably explained by the known characteristics of the 
participant’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the participant; 
o it disappears or decreases on cessation or reduction in dose (note that there are 
exceptions when an AE does not disappear upon discontinuation of the study 
intervention, yet study intervention relatedness clearly exists; for example, as in 
bone marrow depression, fixed study intervention eruptions, or tardive 
dyskinesia); or 
o it follows a known pattern of response to the study intervention(s). 
• Definitely Related: This category applies to those AEs that the Investigator believes are 
incontrovertibly related to study intervention(s). An AE may be assigned an attribution of 
definitely related if or when it meets all of the following criteria: 
o it follows a reasonable temporal sequence from administration of the study 
intervention(s); 
o it could not be reasonably explained by the known characteristics of the 
participant’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the participant; 
o it disappears or decreases on cessation or reduction in dose and recurs with 
re-exposure to study intervention(s) (if rechallenge occurs); and 
o it follows a known pattern of response to the study intervention(s). 
 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 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 on the eCRF. 
• The Investigator will submit any updated data related to SAEs or AESIs to the Sponsor 
within 24 hours of receipt of the information. 
 

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10.5.4 
Reporting of AEs, SAEs, and Other Reportable Safety Events to 
the Sponsor 
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor via an 
Electronic Data Collection Tool  
• The primary mechanism for reporting AEs to the Sponsor will be via the electronic data 
collection (EDC) tool. 
• Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent). 
• If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper AE reporting tool (see next section). 
• Reference Section 8.3.1 – Time Period and Frequency for Collecting AE, AESI, SAE, and 
Other Reportable Safety Event Information for reporting time requirements  
• After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data. 
• The site will report all AESIs, as applicable, on the study-specific SAERF to the Parker 
Institute for Cancer Immunotherapy Pharmacovigilance Group within 24 hours of site 
awareness. The AESI should also be reported on the Adverse Event eCRF. 
• The site will report all SAE data on the study-specific SAERF to the Parker Institute for 
Cancer Immunotherapy Pharmacovigilance Group within 24 hours of site awareness. 
• Contacts for reporting SAEs, AESIs, and other reportable safety events can be found in 
Section 8.3.8.2. 
 
SAE and Other Reportable Safety Event Reporting to the Sponsor 
• In the instance where an SAE or AESI occurs, a facsimile transmission of the SAERF 
and/or Pregnancy Report Form is the preferred method to transmit this information to the 
Parker Institute for Cancer Immunotherapy Pharmacovigilance Group. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAERF sent via email. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAERF within the designated reporting time frames. 
• Contacts for SAE, AESI, and other reportable safety event reporting can be found in 
Section 8.3.8.2. 
 

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10.5.5 
Additional Reporting Considerations 
AE and SAE Recording for Special Circumstances 
Diagnosis versus Signs and Symptoms 
• A diagnosis (if known) or cause of death should be recorded on the Adverse Event eCRF 
page rather than individual signs and symptoms (eg, record only liver failure or hepatitis 
rather than jaundice, asterixis, and elevated transaminases). 
• If a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
separately on the Adverse Event eCRF page. 
• If a diagnosis is subsequently established, all previously reported AEs based on signs and 
symptoms should be nullified and replaced by one AE report based on the single diagnosis, 
with a starting date that corresponds to the starting date of the first symptom of the 
eventual diagnosis. 
Adverse Events That Are Secondary to Other Events 
• In general, AEs that are secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious 
secondary events. A medically significant secondary AE that is separated in time from the 
initiating event should be recorded as an independent event on the Adverse Event eCRF 
page. For example: 
o If vomiting results in mild dehydration with no additional treatment in a healthy 
adult, only vomiting should be reported on the eCRF. 
o If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF. 
o If a severe gastrointestinal hemorrhage leads to renal failure, both events should 
be reported separately on the eCRF. 
o If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
o If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
• All AEs should be recorded separately on the Adverse Event eCRF page if it is unclear 
as to whether the events are associated. 

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Persistent or Recurrent Adverse Events 
• A persistent AE is one that extends continuously, without resolution, between participant 
evaluation time points. Such events should only be recorded once on the Adverse Event 
eCRF page. The initial severity (intensity or grade) of the event will be recorded at the 
time the event is first reported. 
• If a persistent AE becomes more severe, the most extreme severity should also be recorded 
on the Adverse Event eCRF page, and details regarding any increases or decreases in 
severity will be captured on the Adverse Event eCRF. 
• If the event becomes serious, it should be reported to the Sponsor as a SAE, and the 
Adverse Event eCRF page should be updated by changing the event from “non-serious” to 
“serious,” providing the date that the event became serious, and completing all data fields 
related to SAEs. 
• A recurrent AE is one that resolves between participant evaluation time points and 
subsequently recurs. Each recurrence of an AE should be recorded as a separate event on 
the Adverse Event eCRF page. 
Abnormal Laboratory Values 
• A clinical laboratory test value must be reported as an AE if it meets any of the following 
criteria: 
o is accompanied by clinical symptoms 
o results in a change in study intervention (eg, dose modification, treatment 
interruption, or treatment discontinuation) 
o results in a medical intervention or change in concomitant medication 
o is clinically significant in the Investigator’s judgment 
Abnormal Vital Sign Values 
• Medical and scientific judgment should be exercised in deciding whether an isolated vital 
sign abnormality should be classified as an AE. 
• If a clinically significant vital sign abnormality is a sign of a disease or syndrome (eg, high 
blood pressure), only the diagnosis (ie, hypertension) should be recorded on the Adverse 
Event eCRF page. 
• Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF page (see above for details on 
recording persistent AE). 

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Abnormal Liver Function Tests 
• The finding of an elevated alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) (> 3 x baseline value) in combination with either an elevated total bilirubin 
(> 2 x upper limit of normal [ULN]) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s Law). Therefore, Investigators must report as an AE the occurrence of 
either of the following: 
o Treatment-emergent ALT or AST > 3 x baseline value in combination with 
total bilirubin > 2 x ULN (of which ≥ 35% is direct bilirubin) 
o Treatment-emergent ALT or AST > 3 x baseline value in combination with 
clinical jaundice 
• The most appropriate diagnosis or if a diagnosis cannot be established, the abnormal 
laboratory values should be recorded on the Adverse Event eCRF page and reported to the 
Sponsor immediately, either as an SAE or an AESI (as applicable and as defined in the 
cohort appendix for each respective combination). 
Lack of Efficacy or Worsening of Underlying Disease 
• Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. These data will be captured as efficacy 
assessment data only. In most cases, the expected pattern of progression will be based on 
the PCWG3-modified RECIST 1.1 used in this study. In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration. However, every effort 
should be made to document progression through use of objective criteria. If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported as an 
AE. 
Deaths 
• All deaths that occur during the protocol-specified AE reporting period, regardless of 
relationship to study intervention, must be recorded on the Death eCRF page and 
immediately reported to the Sponsor (see Section 8.3.1), unless the death is attributed to 
progression of disease. 
• Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF page. Generally, only one such event should be 
reported. 
• If the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF page. 
• If the cause of death later becomes available (eg, after autopsy), “unexplained death” 
should be replaced by the established cause of death. 
• The term “sudden death” should not be used unless combined with the presumed cause of 
death (eg, “sudden cardiac death”). 

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• If the death is attributed to progression of underlying disease, “underlying disease” should 
be recorded on the appropriate eCRF page; no SAERF is necessary. 
• Deaths that occur after the AE reporting period should be reported as described in 
Section 8.3.2. 
Pre-existing Medical Conditions 
• A pre-existing medical condition is one that is present at the baseline visit for this study. 
Such conditions should be recorded on the Medical History eCRF page. 
• A pre-existing medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the Adverse Event eCRF page, it is important to convey the concept that the pre-
existing condition has changed by including applicable descriptors (eg, “more frequent 
headaches”). 
Adverse Events Associated with Overdose or Error in Drug Administration 
• Overdose should be reported as specified in Section 8.4. 
• All AEs associated with an overdose or incorrect administration of study intervention 
should be recorded on the Adverse Event eCRF page. 
• If the associated AE fulfills seriousness criteria, the event should be reported to the 
Sponsor as a separate SAE. 
 

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10.6 
APPENDIX 6: CONTRACEPTIVE GUIDANCE AND 
COLLECTION OF PREGNANCY INFORMATION 
It is acknowledged that only men will be enrolled in this study. Although women will not be 
enrolled, participants in this study may have female partners of childbearing potential. Therefore, 
sections have been included in this appendix to provide information relevant to women of 
childbearing potential (WOCBP) who may be partners of study participants. 
10.6.1 
Definitions 
10.6.1.1 
Woman of Childbearing Potential 
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 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o 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. 
3. Postmenopausal female 
o 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, a single FSH measurement 
is insufficient.  
o Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT while their partner participates in the study. 
 
10.6.2 
Contraception Guidance 
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 the cohort appendix 
for each respective combination):  

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• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
• Agree to use a male condom plus partner use of a contraceptive method with a failure rate 
of <1% per year as described in Appendix Table 6 when having penile-vaginal 
intercourse with a WOCBP who is not currently pregnant. In addition, male participants 
must refrain from donating sperm for the duration of the study and for 5 half-lives after 
the last dose of study intervention. 
 
Male participants 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 during 
the protocol-defined time frame and for 5 half-lives after the last dose of study intervention. 
Appendix Table 6: 
Highly Effective Contraceptive Methods for Partner Use 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• Oral  
• Intravaginal  
• Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable 
Highly Effective Methods That Are User Independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• 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. 

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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 intervention. 
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:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study intervention, 
which may reduce the efficacy of the contraceptive method. In this case, two highly 
effective methods of contraception should be utilized during the treatment period and for at 
least 5 half-lives after the participant’s last dose of study intervention 
 
10.6.3 
Collection of Pregnancy Information from Male Participants with 
Partners who Become Pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 

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10.7 
APPENDIX 7: GENETICS 
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may 
be due to genetic determinants that impact immune response, 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 blood and tumor sample will be collected for DNA 
analysis from consenting participants. 
• DNA samples will be used for research related to study intervention and/or mCRPC and 
related diseases or evaluation of new assay technologies. They may also be used to 
develop tests/assays including diagnostic tests related to study intervention and/or 
therapies of this drug class and/or immuno-oncology therapies and mCRPC. 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). 
• Stool samples will be collected, and microbiome nucleic acid extracted and analyzed to 
evaluate a participant's response to study intervention, susceptibility to, and severity and 
progression of disease. Variable response to study intervention may be due to bacterial 
genetic determinants that impact immune response, drug absorption, distribution, 
metabolism, and excretion; or by the mechanism of action of the drug. 
• DNA samples may be analyzed for whole genome sequencing and bacterial DNA may be 
analyzed by 16s and/or whole metagenomic sequencing and relationship to clinical 
outcomes in response to study intervention. Additional analyses may be conducted if it is 
hypothesized that this may help further understand the clinical data and/or treatment of 
mCRPC. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand study disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained while research on study intervention or study interventions 
of this class or indication (eg, immunotherapy) continues in accordance with applicable 
law. 

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10.8 
APPENDIX 8: LISTS OF TERMINOLOGY AND 
ABBREVIATIONS 
10.8.1 
List of Terminology 
Terminology 
Description 
Cohort 
A group of participants receiving the same immunotherapy 
combination. 
Cohort appendix 
A document that guides the treatment of participants in a given 
cohort. The cohort appendices are identified using a letter 
designation (eg, Appendix Cohort A, Appendix Cohort B, 
etc.).  
Core protocol 
The master document that provides the elements common 
across the study and among all cohorts, unless otherwise 
specified. 
Immunotherapy combination 
Two or more study interventions administered to a cohort of 
participants. 
 
10.8.2 
List of Abbreviations 
Abbreviation 
Definition 
ADA 
anti-drug antibody(ies) 
ADT 
androgen deprivation therapy 
AE(s) 
adverse event(s) 
AESI(s) 
AE(s) of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BCG 
bacille Calmette-Guerin 
BUN 
blood urea nitrogen 
C 
cycle 
Cmax 
maximum observed drug concentration 
cfDNA 
cell-free deoxyribonucleic acid 
CI(s) 
confidence interval(s) 
CIOMS 
Council for International Organizations of Medical Sciences 
CNS 
central nervous system 
COA 
clinical outcomes assessment 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
complete response 
CSR 
clinical study report 
CT 
computerized tomography 
CTC 
circulating tumor cells 

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Abbreviation 
Definition 
CTC0 
a measure of zero CTC 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DCR 
disease control rate 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data collection 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
GU 
genitourinary 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
health-related quality of life 
HRT 
hormone (hormonal) replacement therapy 
I/E 
inclusion/exclusion 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous(ly) 
LDH 
lactate dehydrogenase 
mCRPC 
metastatic castration-resistant prostate cancer 
MDSC(s) 
myeloid-derived suppressor cell(s) 
MMR 
mismatch repair 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
NCI 
National Cancer Institute 
NK 
natural killer 
NLCB 
no longer clinically benefiting 

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Abbreviation 
Definition 
NLR 
neutrophil/lymphocyte ratio 
nmCRPC 
nonmetastatic castration-resistant prostate cancer 
ORR 
objective response rate 
OS 
overall survival 
OTC 
over-the-counter 
PAP 
prostatic acid phosphatase 
PBMC(s) 
peripheral blood mononuclear cell(s) 
PCWG2 
Prostate Cancer Clinical Trials Working Group 2 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programed cell death ligand 1 
PET 
positron emission tomography 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PORTER 
Prostate Researching Translational Endpoints Correlated to Response 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q3M 
every 3 months 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
rPFS 
radiographic progression-free survival 
SAC 
Safety Assessment Committee 
SAE(s) 
serious adverse event(s) 
SAERF 
Serious Adverse Event Report Form 
SAP 
statistical analysis plan 
SD 
stable disease 
SOA 
Schedule of Activities 
SRE(s) 
skeletal-related event(s) 
SSE(s) 
symptomatic skeletal event(s) 
SUSAR 
suspected unexpected serious adverse reactions 
TC-99m 
technetium-99m 
Treg(s) 
regulatory T cell(s) 
TSH 
thyroid stimulating hormone 

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Abbreviation 
Definition 
ULN 
upper limit of normal 
US 
United States 
VISTA 
V-domain Ig suppressor of T cell activation 
vs 
versus 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 
 

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10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY 
 
DOCUMENT HISTORY 
Documents 
Date of Issue 
Amendment 2 
30 April 2019 
Amendment 1 
24 Jan 2019 
Original Protocol 
07 Dec 2018 
 
 

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