Clinical Study of Bioactivity of Low Dose Apalutamide in Prostate Cancer Patients Scheduled for Prostatectomy
Phase: PHASE2
Conditions: Localized Prostate Carcinoma, Prostate Adenocarcinoma, Stage I Prostate Cancer AJCC v8, Stage II Prostate Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)

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PROTOCOL TRACKING SHEET 
 
 
 
VERSION NUMBER 
VERSION DATE 
REASON FOR CHANGE 
(high-level) 
V6.4 
July 6, 2022 
Updated statistical plan and 
sample size. 
Addition of GWU as an accruing 
site. 
Updated to most recent DCP 
template. 
V6.5 
September 13, 2022 
Updated section 15.4 per CIRB 
review – clarification of 
statistical plan 
V6.6 
October 5, 2022 
Updated version number and 
date due to CIRB required 
changes. 
V6.7 
February 21, 2023 
Extended the study follow-up to 
capture late onset adverse 
events and added the option of 
remote consent; updated to DCP 
protocol template version 12. 
V6.8 
April 4, 2023 
Updates per DCP consensus 
review dated 3/9/23. 
 
 
 

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COVER PAGE 
 
DCP Protocol #: 
UAZ20-01-01  
Local Protocol #: 2102475889 
 
Clinical Study of Bioactivity of Low Dose Apalutamide in Prostate Cancer  
Patients Scheduled for Prostatectomy 
 
 
Lead Academic Organization (LAO) Name: University of Arizona Cancer Prevention Clinical 
Trials Network (CP-CTNet) 
 
 
 
 
Name of LAO Principal  
 
University of Arizona 
Investigators:  
 
 
Sherry Chow, PhD (contact PI) and Julie Bauman, MD, MPH 
 
 
 
 
 
1515 N Campbell Ave 
 
 
 
 
 
Tucson, AZ 85724 
Tel: 520-626-3358 
Fax: 520-626-5348 
schow@azcc.arizona.edu 
 
Organization Name: 
 
 
University of Arizona (AZ163) 
Protocol Principal Investigator: 
Juan Chipollini, MD 
 
 
 
 
 
Clinical Assistant Professor of Urology 
 
 
 
 
 
1501 N Campbell Ave 
 
 
 
 
 
Tucson, AZ 85724 
 
 
 
 
 
Telephone: (479) 966-6651; Fax: (520) 626-4933 
 
 
 
 
 
jchipollini@surgery.arizona.edu 
 
Organization:  
 
 
University of Arizona (AZ163) 
Investigator:  
 
 
Benjamin R. Lee, MD 
 
 
 
 
 
Professor of Urology 
 
 
 
 
 
1501 N Campbell Ave 
 
 
 
 
 
Tucson, AZ 85724 
 
 
 
 
 
Telephone: (520) 626-6895; Fax: (520) 626-4933 
 
 
 
 
 
brlee@email.arizona.edu 
 
Organization:   
 
 
Johns Hopkins University (MD017) 
Investigator:  
 
 
Christian Pavlovich, MD 
 
 
 
 
 
Professor of Urology 
600 N. Wolfe Street  
Baltimore, Maryland 21297 
 
Telephone: (410) 550-3338; Fax: (410) 550-3341  
 
 
 
 
 
cpavlov2@jhmi.edu 
 
Organization:   
 
 
University of Southern California (CA011) 
Investigator:  
 
 
Mike M. Nguyen, MD, MPH 
 
 
 
 
 
Associate Professor of Clinical Urology 
 
 
 
 
 
1441 Eastlake Ave. 
 
 
 
 
 
Los Angeles, CA 90089 
 
 
 
 
 
Telephone: (323) 865-3041; Fax: (323) 865-0120 
 
Mike.Nguyen@med.usc.edu 

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Organization:   
 
 
NCI Clinical Center for Cancer Research (NCICCR) 
Investigator: 
Peter A. Pinto, M.D. 
10 Center Drive 
Building 10, Room 2W-5940 
Bethesda, Maryland 20892-1210 
Tel: (301) 496-6353 
Fax: (301) 402-0922 
 
 
 
pintop@mail.nih.gov 
 
Organization:   
 
 
George Washington University (DC014) 
Investigator: 
Michael J. Whalen, M.D. 
2150 Pennsylvania Ave NW, Suite 3-417 
Washington, DC 20037 
Tel: 202-741-3121  
Fax: 202-741-3113  
 
 
 
mwhalen@mfa.gwu.edu 
 
Organization:  
 
 
University of Arizona  
Statistician: 
 
 
 
Paul Hsu, PhD  
 
 
 
 
 
The University of Arizona Cancer Center 
 
1515 N. Campbell Ave. 
 
Tucson, AZ 85724 
 
Telephone: (520) 626-5054; Fax: (525) 626-2767 
 
 
 
pchhsu@email.arizona.edu 
 
Organization Name: 
NCI/Division of Cancer Prevention 
Medical Monitor: 
 
 
Edward Sauter, MD, PhD  
 
 
 
 
 
National Cancer Institute, Division of Cancer Prevention 
 
 
 
 
 
9609 Medical Center Dr., Rm 5E326 
 
 
 
 
 
Rockville, MD 20850 
 
 
 
 
 
Phone: (240) 276-7657 
 
 
 
 
 
Cell: (240) 944-3279 
 
 
 
                    edward.sauter@nih.gov 
 
Scientific Lead: 
 
 
Chen S. Suen, PhD 
 
 
 
 
 
National Cancer Institute, Division of Cancer Prevention 
9609 Medical Center Drive, 5E-304 
Rockville, MD 20850 
240-276-7095  
 
 
 
chen.suen@nih.gov 
 
Nurse Consultant: 
 
 
Maggie House, RN, BSN 
National Cancer Institute, Division of Cancer Prevention 
9609 Medical Center Drive, 5E-306 
Rockville, MD 20850 
240-276-7047 
240-276-7828 (fax) 
 
 
 
                    housem@mail.nih.gov 
 

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IND Sponsor:
NCI/Division of Cancer Prevention
IND#
Agent(s)/Supplier:
Apalutamide/commercial sources
Protocol Version Date:04/04/2023
Protocol Revision or 
Amendment #
Version 6.8

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SCHEMA 
 
Clinical Study of Bioactivity of Low Dose Apalutamide in Prostate Cancer  
Patients Scheduled for Prostatectomy 
Men with histologically confirmed organ-confined adenocarcinoma of the prostate scheduled for prostatectomy; 
Gleason score ≤ (4+4=8) and current serum PSA ≤ 20 ng/ml.  
Visit 1 - Screening/Baseline Visit 
Informed consent; medical records release form to obtain the biopsy/prostatectomy tissues, pathology reports and 
prior PSA test results; medical history; concomitant medications; baseline signs and symptoms; Karnofsky 
performance status; height; weight; vital signs; blood for clinical labs, PSA, TSH, testosterone, and plasma 
apalutamide assay (the blood draw for testosterone should occur between 7-10 AM for men < 45 years of age and 
prior to 2 PM for men ≥ 45 years of age. If the schedule is not feasible, the blood draw may be scheduled for another 
day); baseline tobacco/alcohol questionnaires, the Expanded Prostate Cancer Index Composite for Clinical Practice 
(EPIC-CP) questionnaire, and COVID-19 assessment. 
 
Agent Initiation 
The study is expected to have 2 dose groups. Participants in the first dose group will receive apalutamide 60 mg 
MWF for 4-8 weeks prior to prostatectomy.  Based on the PSA response, an additional group of participants will 
receive de-escalated dose at 60 mg once per week, or escalated dose at 60 mg daily for 4-8 weeks prior to 
prostatectomy. For each dosing regimen, the participant will take a loading dose (3 x 60 mg) the first day of 
agent intervention to reach the steady-state drug levels sooner. Participants may receive the agent intervention 
up to 12 weeks if the surgery is delayed. 
 
 
Participant Contact 
Participants will be contacted during the first week of agent intervention to assess compliance and safety and then 
every 7-10 days for the duration of the study. Participants will be contacted prior to Visit 2 to remind them of the 
upcoming appointment and to hold that day’s dose of study agent until after their blood draw.  
 
 
Visit 2 – End-of-Intervention Visit  
 (within 3 days prior to surgery) 
Blood draw for clinical labs, PSA, TSH, and testosterone, and plasma apalutamide assay (the blood draw for 
testosterone should occur between 7-10 AM for men < 45 years of age and prior to 2 PM for men ≥ 45 years of age); 
concomitant medications (conmeds) and adverse events (AEs) evaluation; agent compliance assessment; follow-up 
tobacco/alcohol questionnaires; EPIC-CP questionnaire; COVID-19 assessment; collect study agent, AE diary, and 
agent intake calendar if this visit occurs the day before surgery. Collection of new AEs and concomitant medications 
ends with the operative day. 
 
 
Visit 3 - Post-intervention Follow-up Visit 
(7-14 days post-prostatectomy and may be combined with the postoperative appointment for catheter removal) 
Blood draw to assess testosterone levels (should occur between 7-10 AM for men < 45 years of age and prior to 2 
PM for men ≥ 45 years of age); collect study agent, AE diary, and agent intake calendar if not done at the End-of-
Intervention visit. Request paraffin-embedded pre-intervention biopsy 
and prostatectomy tissue blocks or slides from respective pathology labs. 
 
 
Extended Post-intervention Follow-up 
(60 (± 5) days post-prostatectomy) 
Participants will be contacted by their preferred method(s) to capture late onset adverse events.  
 
 
 

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Endpoints 
Primary endpoint: effects of low dose apalutamide on circulating PSA levels. 
Secondary endpoints: reversibility of testosterone levels 7-14 days post-intervention (post-operative), post-
intervention plasma trough apalutamide concentrations, health-related quality of life (HRQOL).  
Exploratory endpoints: intra-prostatic immune cell infiltration, change in Gleason score, tobacco/alcohol use on 
study endpoints. 
 
 

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TABLE OF CONTENTS
PROTOCOL TRACKING SHEET ...............................................................................................................i 
COVER PAGE.............................................................................................................................................. 2 
SCHEMA...................................................................................................................................................... 5 
1.        OBJECTIVES............................................................................................................................................10 
1.1 
Primary Objectives ....................................................................................................................................10 
1.2        Secondary Objectives ..............................................................................................................................10 
1.3       Exploratory Objectives.............................................................................................................................10 
2. 
BACKGROUND ................................................................................................................................ 10 
2.1 
Prostate Cancer ..........................................................................................................................................10 
2.2 
Apalutamide...............................................................................................................................................10 
2.3 
Rationale....................................................................................................................................................12 
3. 
SUMMARY OF STUDY PLAN........................................................................................................ 14 
4. 
Participant SELECTION .................................................................................................................... 15 
4.1 
Inclusion Criteria .......................................................................................................................................15 
4.2 
Exclusion Criteria ......................................................................................................................................16 
4.3 
Inclusion of Women and Minorities ..........................................................................................................17 
4.4  
Recruitment ...............................................................................................................................................17 
4.5  
Planned Accrual.........................................................................................................................................18 
1. 
REGISTRATION PROCEDURES .................................................................................................... 18 
5.1   Investigator and Research Associate Registration with CTEP ..................................................................18 
6. 
NCI CENTRAL INSTITUTIONAL REVIEW BOARD ................................................................... 19 
7. 
AGENT ADMINISTRATION ........................................................................................................... 19 
7.1 
Dose Regimen and Dose Groups ...............................................................................................................20 
7.2 
Apalutamide Administration......................................................................................................................20 
7.3 
Run-in Procedures .....................................................................................................................................20 
7.4 
Contraindications.......................................................................................................................................20 
7.5 
Concomitant Medications..........................................................................................................................20 
7.6 
Dose Modification .....................................................................................................................................21 
7.7 
Adherence/Compliance..............................................................................................................................21 
8. 
PHARMACEUTICAL INFORMATION........................................................................................... 21 
8.1 
Apalutamide (IND #
 IND Sponsor NCI, Division of Cancer Prevention)....................................21 
8.2 
Reported Adverse Events and Potential Risks...........................................................................................22 
8.3  
Availability ................................................................................................................................................23 
8.4 
Agent Distribution .....................................................................................................................................23 
8.5  
Agent Accountability.................................................................................................................................23 
8.6 
Packaging and Labeling.............................................................................................................................23 
8.7 
Storage.......................................................................................................................................................24 
8.8 
Registration/Randomization ......................................................................................................................24 
8.9 
Blinding and Unblinding Methods.............................................................................................................25 
8.10 Agent Destruction/Disposal.......................................................................................................................25 
9.  
CLINICAL EVALUATIONS AND PROCEDURES........................................................................ 25 
9.1 
Schedule of Events ....................................................................................................................................25 
9.2 
Baseline Testing/Pre-Study Evaluation .....................................................................................................26 
9.3 
Evaluation During Study Intervention.......................................................................................................26 
9.4 
Evaluation at Completion of Study Intervention .......................................................................................26 
9.5 
Post-intervention Follow-up Period...........................................................................................................27 
9.6 
Methods for Clinical Procedures ...............................................................................................................27 
10.  CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION ................................................ 28 
10.1 Primary Endpoint.......................................................................................................................................28 
10.2 Secondary Endpoints .................................................................................................................................28 
10.3 Exploratory Endpoints...............................................................................................................................28 
10.5 Off-Study Criteria......................................................................................................................................29 

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10.6 Study Termination ..................................................................................................................................... 29 
11. CORRELATIVE/SPECIAL STUDIES .............................................................................................. 29 
11.1 Rationale for Methodology Selection ........................................................................................................ 29 
11.2 Comparable Methods ................................................................................................................................. 29 
12. SPECIMEN MANAGEMENT ........................................................................................................... 29 
12.1 Laboratories ............................................................................................................................................... 29 
12.2 Collection and Handling Procedures ......................................................................................................... 30 
12.3 Shipping Instructions ................................................................................................................................. 30 
12.4 Tissue Banking .......................................................................................................................................... 31 
13. REPORTING ADVERSE EVENTS .................................................................................................. 31 
13.1 Adverse Events .......................................................................................................................................... 31 
13.2 Serious Adverse Events ............................................................................................................................. 33 
14. STUDY MONITORING .................................................................................................................... 34 
14.1 Data Management ...................................................................................................................................... 34 
14.2   Electronic Case Report Forms ................................................................................................................... 34 
14.3 Source Documents ..................................................................................................................................... 35 
14.4 Data and Safety Monitoring Plan ............................................................................................................... 35 
14.5 Sponsor or FDA Monitoring ...................................................................................................................... 35 
14.6 Record Retention ....................................................................................................................................... 35 
14.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) ......... 36 
15. STATISTICAL CONSIDERATIONS ............................................................................................... 36 
15.1 Study Design/Description .......................................................................................................................... 36 
15.2 Randomization/Stratification ..................................................................................................................... 37 
15.3 Sample Size ............................................................................................................................................... 37 
15.4 Primary Objective, Endpoint(s), Analysis Plan ......................................................................................... 37 
15.5 Secondary Objectives, Endpoints, Analysis Plans ..................................................................................... 38 
15.6 Reporting and Exclusions .......................................................................................................................... 39 
15.7 Evaluation of Toxicity ............................................................................................................................... 39 
15.8 Evaluation of Response ............................................................................................................................. 40 
15.9 Interim Analysis......................................................................................................................................... 40 
15.10 Ancillary Studies ....................................................................................................................................... 40 
16. REGULATORY And ETHICAL CONSIDERATIONS .................................................................... 40 
16.1 Required Documents ................................................................................................................................. 40 
16.2 Informed Consent ...................................................................................................................................... 40 
16.3 Collection of Regulatory Documents ......................................................................................................... 41 
16.4 Other .......................................................................................................................................................... 41 
17.  ROSTER MANAGEMENT ............................................................................................................... 41 
18. FINANCING, EXPENSES, AND/OR INSURANCE ........................................................................ 42 
REFERENCES ........................................................................................................................................... 42 
APPENDIX A PERFORMANCE STATUS CRITERIA ........................................................................... 45 
APPENDIX B ............................................................................................................................................. 46 
ALCOHOL AND TOBACCO QUESTIONNAIRE INSTRUCTIONS ............................................................... 46 
ALCOHOL ASSESSMENT-- BASELINE .......................................................................................................... 47 
ALCOHOL ASSESSMENT - FOLLOW-UP ...................................................................................................... 50 
TOBACCO ASSESSMENT – BASELINE ......................................................................................................... 52 
TOBACCO ASSESSMENT - FOLLOW-UP ...................................................................................................... 56 
NATIONAL AND LOCAL RESOURCES TO HELP WITH ALCOHOL ABUSE AND ALCOHOLISM....... 59 
NATIONAL AND LOCAL RESOURCES TO HELP WITH QUITTING SMOKING ...................................... 60 
APPENDIX C ............................................................................................................................................. 61 
EXPANDED PROSTATE CANCER INDEX COMPOSITE FOR CLINICAL PRACTICE (EPIC-CP) ........... 61 
APPENDIX D ............................................................................................................................................. 64  
 
PARTICIPANT CLINICAL TRIAL WALLET CARD ............................................................................. 64 
APPENDIX E ............................................................................................................................................. 65 
LIST OF DRUGS IN CATEGORY X DRUG INTERACTIONS ....................................................................... 65 

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APPENDIX F.............................................................................................................................................. 66 
COVID 19 ASSESSMENT INSTRUCTIONS ........................................................................................................... 66 
CP-CTNET COVID-19 BASELINE ASSESSMENT ................................................................................................. 67 
CP-CTNET COVID-19 FOLLOW-UP ASSESSMENT ............................................................................................. 70 
APPENDIX G  REMOTE CONSENT INSTRUCTIONS ......................................................................... 73 

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1.        OBJECTIVES 
 
1.1       Primary Objectives  
The primary objective is to determine the effects of low dose apalutamide on circulating levels of Prostate 
Specific Antigen (PSA). 
 
1.2        Secondary Objectives  
The secondary objectives, in the order of priority, are to determine the effect of low dose apalutamide on  
• 
Reversibility of testosterone levels 7-14 days post intervention 
• 
Post-intervention plasma trough apalutamide concentration  
• 
Health-related quality of life.  
 
1.3       Exploratory Objectives 
The exploratory objectives are to determine the effects of apalutamide on intra-prostatic immune cell 
infiltration and Gleason score and the effects of tobacco/alcohol use on the study endpoints. 
 
2. 
BACKGROUND 
 
2.1 
Prostate Cancer 
 
Clinically localized prostate cancer is managed primarily through surgery or radiation therapy. Population 
studies suggest that a substantial proportion of men diagnosed with localized prostate cancer in the US are 
over-treated [1-3]. This public health problem—unnecessarily aggressive treatment of tens of thousands 
of men each year who subsequently suffer chronic side effects—challenges us to develop innovative 
therapeutic models to refine treatment paradigms within this patient population. In recent years, active 
surveillance has increasingly garnered attention as an alternative, and less morbid, approach to surgery or 
radiation in men with clinically localized, low-risk prostate cancer. Follow-up assessments in patients on 
active surveillance include serial PSA measures, repeat prostate biopsy and, increasingly, prostate MRI.  
Most men on active surveillance followed for up to 15 years will not require treatment. However, up to 
one-third of active surveillance patients will undergo treatment within 2 to 5 years of initiating 
surveillance [4].  
 
Development of intervention strategies to prevent disease progression in patients on active surveillance 
thus represents an important area of prostate cancer chemoprevention. 
 
2.2 
Apalutamide 
 
The androgen receptor (AR) signaling axis plays a critical role in the development, function and 
homeostasis of the prostate [5]. The classical action of AR is to regulate gene transcriptional processes via 
AR nuclear translocation, binding to androgen response elements on target genes and recruitment of, or 
crosstalk with, transcription factors. Prostate cancer initiation and progression is also uniquely dependent 
on AR.  
 
Due to the critical role of AR signaling in the pathophysiology of prostate cancer, treating patients on 
active surveillance with an AR inhibitor may be a potential approach to prevent disease progression. 
However, the first-generation of AR antagonists such as flutamide, bicalutamide, and nilutamide and the 
next generation AR inhibitors such as enzalutamide have various adverse effects that preclude extended 
use in prevention settings.  
 
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cancer (nmCRPC) and for metastatic castration-sensitive prostate cancer in 2018 and 2019, respectively.  
Apalutamide binds AR in the same ligand-binding domain as bicalutamide but with greater affinity [6]. 
Unlike bicalutamide, it retains full antagonist activity in the setting of AR overexpression. Furthermore, 
apalutamide was shown to be selective for AR versus other nuclear hormone receptors [6]. In mouse 
xenograft tumor models of LNCaP/AR(cs) cells that overexpressed AR, apalutamide was more 
efficacious than bicalutamide and enzalutamide [7]. When assessed in mice, the tumor/plasma ratios of 
apalutamide were significantly higher than tumor/plasma ratios of enzalutamide, possibly due to lower 
plasma protein binding of apalutamide, allowing for more tissue distribution [6]. Both apalutamide and 
enzalutamide are weak antagonists of J-aminobutyric acid receptors in the brain, which is thought to 
contribute to enzalutamide-associated seizure. However, the penetration through the blood-brain barrier 
appears to be different between the two agents as the brain concentrations of apalutamide was lower than 
that of enzalutamide [6].  
 
A Phase I study of apalutamide was conducted in 30 patients with progressive mCRPC over the dose 
range of 30 to 480 mg daily [8]. Apalutamide was found to be well tolerated and displayed linear 
pharmacokinetics. No seizures were reported at any dose level. Reduction of uptake of fluoro-5α 
dihydrotestosterone (FDHT) on positron emitted tomography (PET) consistent with saturation of AR 
binding was observed at doses ≥ 120 mg. Across all dose cohorts, ≥ 50% deduction in PSA at 12 weeks 
was observed in 14 of 30 patients, suggesting substantial clinical activity.  A maximum efficacious dose 
of 240 mg daily was selected for Phase II trials based on integration of preclinical and clinical data. 
 
Phase II trials of apalutamide have been conducted in three expansion cohorts: patients with nmCRPC, 
patients with mCRPC who were abiraterone-naïve and patients with mCRPC following treatment with 
abiraterone. In the nmCRPC cohort, apalutamide was well tolerated with fatigue as the most common AE. 
The median treatment duration was 26.9 months, with 89% of patients experiencing a ≥ 50% deduction in 
PSA at 12 weeks. The median time to PSA progression was 24 months [9]. The two cohorts of men with 
mCRPC, the 12-week PSA response rate (at least 50% decline from baseline) was 88% for abiraterone 
naïve patients and 22% for post-abiraterone patients. The median time to PSA progression was 18.2 
months for abiraterone-naïve patients and only 3.7 months for post-abiraterone patients. The median 
duration of apalutamide treatment was 21 months for abiraterone naïve and 4.9 months in the post-
abiraterone cohort. The safety profile in these two cohorts was consistent with previously reported data 
[10].  
 
A Phase III trial of apalutamide in patients with nmCRPC showed that apalutamide significantly 
improved metastasis-free survival compared to placebo (40.5 months versus 16.2 months). Secondary 
endpoint of time to symptomatic progression was also significantly longer with apalutamide than with 
placebo. There was a PSA response for 89.7% of subjects on apalutamide vs. only 2.2% of subjects in 
placebo. The frequency of Aes grade 3 or above was 45.1% in the apalutamide group and 34.2% in the 
placebo group. Only 0.2% (two patients total) treated with apalutamide had a documented seizure, both in 
patients with predisposing conditions [11]. In a Phase III trial involving patients with metastatic, 
castration-sensitive prostate cancer, the addition of apalutamide to androgen deprivation therapy (ADT) 
significantly improved overall survival and radiographic progression-free survival than with placebo plus 
ADT. The frequency of Aes grade 3 or above was 42% in the apalutamide group and 40.8% in placebo, 
with rash more common with apalutamide treatment [12]. 
 
Due to the promising clinical efficacy and improved therapeutic index of apalutamide, NCI, Division of 
Cancer Prevention conducted preclinical studies to assess its prostate cancer preventive activity. The 
preclinical studies were conducted in the Bosland tumor model with tumors induced in male rats by 
sequential administration of antiandrogen (flutamide), androgen (testosterone propionate), and the 
chemical carcinogen N-methyl-N-nitrosourea (MNU), followed by chronic androgen stimulation [13]. 

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Beginning 1 week after MNU administration, animals received apalutamide or vehicle via oral gavage at 
different dosing regimens. Results showed that apalutamide is a highly potent inhibitor of prostate cancer. 
In the vehicle control, the incidence of invasive cancers in the dorsolateral/anterior prostate and all 
accessory sex cancers combined was 47% and 53%, respectively. Cancer incidence in the accessory sex 
glands was 0% in rats receiving either apalutamide at 30 mg/kg/day or 15 mg/kg/day. Intermittent (1 
week on/1 week off) apalutamide at 30 mg/kg/day was also effective in preventing accessory sex gland 
cancers (10% incidence) and cancers confined to the dorsolateral/anterior prostate (3% incidence) but not 
as effective as the continuous daily exposure. Apalutamide was well tolerated at all dose levels (1-30 
mg/kg/day). No mortality was seen in any group. Optimal pharmacodynamic activity evidenced by a 
dose-dependent down-regulation of androgen-dependent genes in the dorsolateral prostate was observed 
at the doses of 15 and 30 mg/kg/day (unpublished results from agent solicitation summary). 
 
The clinical pharmacokinetics of apalutamide have been studied over the dose range of 30 to 480 mg/day 
(0.125 – 2 times the recommended dose) in the Phase I study [8]. Apalutamide was rapidly absorbed with 
peak plasma concentrations occurred 2 to 3 hours after administration. Maximum plasma concentration 
and area under the plasma concentration-time curve (AUC) increased proportionally over the dose range 
studied. Plasma concentrations declined slowly following dosing with a mean half-life of 3 to 4 days. 
Drug half-life and time to steady-state were independent of dose. Plasma trough concentration increased 
steadily with time and in proportion to dose. Most patients reached steady-state exposure after 3 weeks of 
continuous administration with the mean accumulation ratio of 5-fold.  
 
2.3 
Rationale 
 
The promising biological and clinical activity of apalutamide and its improved safety profile established a 
rationale to test this agent for prevention of progression in the active surveillance setting. In addition, the 
long half-life of this drug offers the potential of utilizing an intermittent dosing schedule to further 
minimize its associated side effects. We propose to conduct an open label trial of low dose apalutamide in 
the pre-surgical setting to determine an optimal dosing regimen for further study in men on active 
surveillance.  We hypothesize that low dose apalutamide will be tolerable and lead to favorable 
pharmacodynamic changes in men with localized, low/intermediate risk prostate cancer. 
 
The primary objective of this study is to determine the effects of low dose apalutamide on circulating 
PSA levels. In prior Phase II-III trials in patients with nmCRPC and mCRCP, apalutamide administered 
at 240 mg daily was effective in suppressing circulating PSA levels with greater than 89% of patients 
experiencing a 12-week PSA response (at least 50% decline from baseline) [10, 11]. This study will 
determine whether low dose apalutamide will lead to lowered PSA levels in patients with low and 
intermediate risk prostate cancer.  
Figure 1. Plasma trough levels over time. a. a loading dose of 180 mg and 60 mg QD dosing. b. a loading dose of 180 mg and 60 
mg MWF/wk dosing. c. a loading dose of 180 mg and 60 mg/wk dosing.  
week 1
week 2
week 3
week 4
week 5
0.0
0.5
1.0
1.5
2.0
2.5
Trough [Apalutamide] (ug/mL)
week 1 (day 7)
week 2 (day 14)
week 3 (day 21)
weel 4 (day 28)
0.0
0.2
0.4
0.6
0.8
1.0
Trough [Apalutamide] (ug/mL)
_
g
g
_ p
week 1 (day 7)
week 2 (day 14)
week 3 (day 21)
weel 4 (day 28)
week 5 (day 35)
0.0
0.2
0.4
0.6
0.8
Trough [Apalutamide] (ug/mL)
_
g
g
_ p
a
b
c

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Patients with Gleason score 8 are included because we expect the PSA response (and the response of 
other study endpoints) to low dose apalutamide to be similar to patients with Gleason score 6 and 7. 
However, any Gleason pattern 5 is an exclusion. The prior Phase I study in patients with castration-
resistant prostate cancer showed that apalutamide taken at 60 mg per day resulted in steady-state plasma 
trough apalutamide concentrations similar to plasma concentrations observed at a dose level that led to 
tumor growth inhibition in the murine model of castration-resistant prostate cancer [8]. We have, 
therefore, selected to study the 60 mg dose at different dosing schedules up to 60 mg per day. Due to the 
anticipated short intervention period (4-8 weeks, depending on the surgery schedule), pharmacokinetic 
simulations were performed to select optimal loading dose to reach steady-state drug levels sooner to 
increase the likelihood of observing the drug effects. Figure 1 illustrates the plasma trough levels over 
time with a loading dose of 180 mg for three maintenance dosing schedules (data generated by Dr. Cody 
Peer, NCI Clinical Pharmacology Program). A loading dose of 180 mg for the 60 mg once a day dosing 
schedule will reach steady-state levels at the end of 2 weeks. Similar time to steady-state is achieved with 
a loading dose of 180 mg for the 60 mg q M-W-F dosing schedule. A loading dose of 180 mg for the 60 
mg once a week dosing schedule will allow the target level to be achieved and maintained after the first 
dose. 
 
A recently completed trial of enzalutamide in prostate cancer patients with biochemical recurrence 
showed that elevated testosterone levels with enzalutamide treatment decline rapidly following 
discontinuation of enzalutamide (personal communication provided by NCI, DCP).  This study will assess 
the reversibility of circulating testosterone levels after low dose apalutamide. We also plan to assess the 
plasma trough apalutamide levels and to determine whether the systemic drug levels correlate with the 
PSA response.  
 
Suppression of androgen signaling has been reported to lead to immune-stimulatory effects (reviewed in 
[14]). Clinical studies have shown that androgen deprivation therapy (ADT) induces expansion of naïve T 
cells and increases T-cell responses in peripheral blood mononuclear cells [15]. ADT is also associated 
with infiltration of T-cells, macrophages, and nature killer cells into the prostate [16-18]. Prior preclinical 
studies demonstrated that ADT enhances susceptibility of AR-overexpressing prostate cancer cells to 
immune-mediated T-cell killing through improved immune recognition [19, 20]. Emerging clinical data 
also reveals that ADT could enhance the efficacy of various immunotherapies [21-23]. A number of 
ongoing trials are evaluating the combination of ADT and/or inhibitors of androgen receptor or androgen 
synthesis with different immunotherapies.  This study offers the opportunities to determine whether low 
dose apalutamide will lead to changes in intra-prostatic immune cell infiltration.  
 
Furthermore, this study will determine the effects of low dose apalutamide on health-related quality of 
life. This information will help inform the feasibility of implementing low dose apalutamide in patients 
undergoing active surveillance. 
 
In addition, the study will explore the effects of apalutamide on Gleason score of pre- and post-
intervention tumor(s) with matched location. It is expected that such materials will only be available in a 
subgroup of participants where pathology review can be performed on ex vivo prostate tissue sample 
collected at prostatectomy from the tumor(s) that MRI directed biopsies were collected prior to 
enrollment. 
 
Increasing evidence suggests that tobacco and alcohol use are risk factors in the development of 
intraepithelial neoplasia and cancer. In addition, tobacco and alcohol use may adversely affect agent 
intervention, for example by altering the safety profile or metabolism of a drug. Standardized assessments 
of tobacco and alcohol use during clinical trials will aid in understanding the potential relationship 
between the use of these products and clinical endpoints or cancer prevention biomarkers. Therefore, 

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NCI, DCP is including assessment of tobacco and alcohol use at baseline and post-intervention, to 
determine the potential impact of tobacco and alcohol use on 1) treatment toxicity and symptom burden, 
and 2) the efficacy of treatment intervention. 
 
The NCI, DCP Assessment of COVID-19 exposure and vaccine status at baseline and end of study will 
be used to determine the potential impact on 1) treatment toxicity and symptom burden, and 2) the 
efficacy of treatment intervention. 
 
 
3. 
SUMMARY OF STUDY PLAN 
 
We propose a Phase IIa open label dose-finding trial of low dose apalutamide in prostate cancer patients 
scheduled to undergo radical prostatectomy.  The study is expected to include 2 dose groups. Up to 
twenty eligible participants will be accrued into each dose group to initiate agent intervention. We 
anticipate accruing 1 participant every two months until all sites are activated. Once all sites are activated, 
we anticipate accruing 1-2 participants every month, we expect to complete the accrual of each dose 
cohort in 20 months.  We plan to recruit men over the age of 18 with good performance status and normal 
renal, hepatic, marrow, and thyroid function. Eligibility disease characteristics include histologically 
confirmed organ-confined adenocarcinoma of the prostate (Pca), Gleason score ≤ (4+4) and current serum 
PSA ≤ 20 ng/ml.  
The exclusion criteria include prior or ongoing hormonal treatment for prostate; prostate cancer with 
distant metastases; presence of neuroendocrine differentiation; serum testosterone < 200 ng/dL; a history 
of prior malignancies other than prostate cancer within the past 2 years, excluding non-melanoma skin 
cancer; severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or 
venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient 
ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to registration; 
history of seizure or known condition that may pre-dispose to seizure;  use of drugs known to lower the 
seizure threshold; receiving any other investigational agents; history of allergic reactions attributed to 
compounds of similar chemical composition of apalutamide;  and uncontrolled intermittent illnesses or 
medical conditions which, in the opinion of the treating physician, would make this protocol 
unreasonably hazardous for the patient. 
Accrued participants in the first dose group will receive apalutamide 60 mg MWF/week for 4-8 weeks 
prior to prostatectomy.  Participants may receive the agent intervention up to 12 weeks if the surgery is 
delayed. Based on the PSA response, an additional cohort of participants will receive a de-escalated 
dosing regimen at 60 mg once per week, or an escalated dosing regimen at 60 mg daily for 4-8 weeks 
prior to prostatectomy. To improve the efficiency of trial conduct, a continuous monitoring plan will be 
used for efficacy/futility evaluation after 12 participants have completed the dosing regimen and the dose 
cohort will be stopped early for efficacy or futility. For each dosing regimen, the participant will take a 
loading dose (3 x 60 mg) on the first day of agent intervention to reach the steady-state drug levels 
sooner.  
 
The agent intervention is not meant to delay the curative surgery. Only patients whose surgery is planned 
to allow for a minimum of 4 weeks and up to 12 weeks of agent intervention will be enrolled. The 
intervention duration will be adjusted depending on the planned surgery schedule. 
 
At the screening/baseline visit, the informed consent form and medical records release form will be 
signed in order to obtain the biopsy/prostatectomy tissues, pathology reports and prior PSA test results. 
Participants will be evaluated for height, weight and vital signs (temperature, pulse, and blood pressure), 
concomitant medications, medical history and baseline symptoms and signs. Baseline blood samples will 

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be collected for CBC-diff, CMP, PSA, TSH, testosterone, and plasma apalutamide assay. The blood draw 
for testosterone should occur between 7-10 AM for men < 45 years of age and prior to 2 PM for men ≥ 45 
years of age because of circadian variation in testosterone levels [33]. If the schedule is not feasible, the 
blood draw may be scheduled for another day. Aliquots of plasma will be stored for plasma apalutamide 
assay. Participants will also complete baseline tobacco/alcohol questionnaires and the Expanded Prostate 
Cancer Index Composite for Clinical Practice (EPIC-CP) questionnaire, and COVID-19 assessment. 
Subjects will be instructed in how to complete the Intake Calendar and Adverse Event Diary. 
 
When eligibility is confirmed from lab results, participants will be provided with the study drug in 
amount sufficient for the entire study duration based on the surgery schedule and the assigned dosing 
regimen plus an extra week of agent supply.  
 
Participants will return to the clinic within 3 days prior to surgery for a post-intervention blood draw for 
CBC-diff, CMP, PSA, TSH, testosterone, and research endpoints. Similarly, the blood draw for 
testosterone should occur between 7-10 AM for men < 45 years of age and prior to 2 PM for men ≥ 45 
years of age. Adverse events, concomitant medications and agent compliance will be assessed. 
Participants will complete the follow-up tobacco/alcohol questionnaires and EPIC-CP questionnaire, and 
COVID-19 assessment. In order to assess the plasma trough apalutamide levels, participants will be asked 
to hold the apalutamide dose on the day of the visit until after the blood draw. 
 
A blood sample will be collected 7-14 days post-prostatectomy to assess reversibility of circulating 
testosterone levels and plasma apalutamide levels. Blood draw for testosterone should occur between 7-10 
AM for men < 45 years of age and prior to 2 PM for men ≥ 45 years. This visit may be combined with the 
postoperative appointment for catheter removal. 
 
Participants will be contacted 60 days (± 5 days) post-prostatectomy by their preferred method of contact 
to capture any late onset adverse events, excluding adverse events that are related to prostatectomy.  
 
At the discretion of the treating urologist, a testosterone test may be repeated at the 3-month post-surgery 
standard-of-care visit if the testosterone levels remained elevated at Visit 3. The testosterone results will 
be captured through a chart review if this was repeated at the 3-month post-op visit. 
 
Paraffin-embedded pre-intervention biopsy and prostatectomy tissue blocks or slides will be requested 
from respective pathology labs for measurement of secondary tissue biomarkers. 
 
4. 
PARTICIPANT SELECTION 
 
4.1 
Inclusion Criteria  
 
4.1.1 
Histologically confirmed organ-confined adenocarcinoma of the prostate (Pca) suitable for 
prostatectomy. 
 
4.1.2 
Gleason score ≤ (4+4), however no Gleason pattern 5. 
 
4.1.3 
Current serum PSA ≤ 20 ng/ml.  
 
4.1.4 
Age !18 years. 
 
4.1.5 
Karnofsky ≥70%; see Appendix A 
 

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4.1.6 
Participants must meet the following laboratory measures:  
 
x 
Leukocytes  
 
≥3,000/PL 
x 
Absolute neutrophil count 
≥1,500/PL 
x 
Platelets 
 
 
 
≥100,000/PL 
x 
Total bilirubin  
 
≤1.5 x institutional upper limit of normal (ULN) ((note: in 
subjects with Gilbert’s syndrome, if total bilirubin is > 1.5 x ULN, measure direct and 
indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject may be eligible)  
x 
AST (SGOT)/ALT (SGPT) 
<2.5 x institutional ULN 
x 
Creatinine  
 
<2 x institutional ULN 
 
4.1.7 
TSH within the institutional normal range. 
 
4.1.8  Willing to use adequate contraception (barrier method; abstinence; subject has had a vasectomy; 
or partner is using effective birth control or is postmenopausal) for the duration of study participation.  
 
4.1.9  Ability to understand and the willingness to sign a written informed consent document. 
 
4.2 
Exclusion Criteria  
 
4.2.1 
Prior or ongoing hormonal treatment for prostate cancer including, but not limited to 
orchiectomy, antiandrogens, abiraterone, ketoconazole, or estrogens, or luteinizing hormone-releasing 
hormone (LHRH) agonists/antagonists. Men on stable doses of 5-alpha reductase inhibitors (e.g., 
finasteride, dutasteride) are eligible as long as there is no planned dose change while on study. 
4.2.2 
Patients who have prostate cancer with distant metastases. 
4.2.3 
Presence of neuroendocrine differentiation in the prostate biopsies. 
4.2.4 
Serum testosterone (blood collected between 7-10 AM for men < 45 years of age and prior to 2 
PM for men ≥ 45 years of age) < 200 ng/dL. 
4.2.5 
Have a history of prior malignancies other than prostate cancer within the past 2 years, excluding 
non-melanoma skin cancer. 
4.2.6 
Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or 
venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient 
ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to registration. 
 
4.2.7 
History of seizure or known condition that may pre-dispose to seizure (including but not limited 
to prior stroke, transient ischemic attack, loss of consciousness within 1 year prior to registration, brain 
arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are 
causing edema or mass effect).  
 
4.2.8  Use of drugs known to lower the seizure threshold, including: atypical antipsychotics (e.g. 
clozapine, olanzapine, risperidone, ziprasidone), bupropion, lithium, meperidine, pethidine, phenothiazine 
antipsychotics (e.g. chlorpromazine, mesoridazine, thioridazine), and tricyclic antidepressants (e.g. 
amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine). 
 
4.2.9 
Concurrent use of drugs in category X drug interactions with apalutamide (see list in Appendix 
E).  
 
4.2.10 Participants may not be receiving any other investigational agents. 

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4.2.11 History of allergic reactions attributed to compounds of similar chemical composition of 
 
apalutamide. 
 
4.2.12 Uncontrolled intermittent illnesses or medical conditions which, in the opinion of the treating 
physician, would make this protocol unreasonably hazardous for the patient. Such illnesses/conditions 
may include, but are not limited to, hypertension, ongoing or active infection, or psychiatric illness/social 
situations. 
 
4.3 
Inclusion of Women and Minorities 
 
Men of all races and ethnic groups are eligible for this trial. Since women and children are not subject to 
prostate cancer, they will be excluded from this study. 
 
4.4  
Recruitment  
 
Study participants will be recruited from patients seen in the urology clinics at  Johns Hopkins University, 
University of Southern California, George Washington University, NCI Clinical Center for Cancer 
Research, and University of Arizona (Banner/University Medicine).    
 
Depending on the clinic workflow, one or all of the following recruitment strategies will be implemented: 
1. Study investigators (urologic surgeons) and/or their clinic staff will have access to identifiable health 
information of patients seen in the urology clinics. They will screen patients for their potential eligibility. 
The investigators and/or their clinic staff will present the study to potentially eligible patients to assess 
interests in study participation.  
2. Urologic surgeons and/or their clinic staff will make the initial contact (oral or written communication) 
with patients seen in the urologic clinics to assess their interests in being contacted by the research staff 
for a research study.  The names of those who are willing to be contacted will be forwarded to the 
research staff.  The research staff will contact these patients to further describe the study and to assess 
interests and potential eligibility in study participation.   
3. A study information letter will be developed along with the option of allowing the research staff to 
review their identifiable health information to assess their potential eligibility for the study and to contact 
them if they were found potentially eligible. The research staff will contact patients who opt in for contact 
and chart review and are potentially eligible to further describe the study and to assess interests in study 
participation.  
Although this intervention is relatively brief, study personnel will be sensitive to the stress 
participants will likely experience in preparing for a major surgical procedure.  The study team is 
committed to providing a friendly and comfortable study setting for participants from initial 
contact through the completion of their study activities.  Demands upon the subjects will be 
minimized to foster comfort while preserving the research goals.  Wherever possible, flexibility 
will be built into the study schedule to promote compliance and acknowledge the dependence 
upon surgical and hospitalization schedules.  
 
 
 

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4.5  
Planned Accrual 
 
Racial Categories 
Not Hispanic or 
Latino: 
Female 
Not Hispanic or 
Latino: 
Male 
Hispanic or 
Latino: 
 
Female 
Hispanic or 
Latino: 
 
Male 
 
Total 
American Indian/Alaska Native 
- 
1 
- 
0 
1 
Asian 
- 
3 
- 
0 
3 
Native Hawaiian or Other Pacific 
Islander 
- 
1 
- 
0 
1 
Black or African American 
- 
5 
- 
1 
6 
White  
- 
22 
- 
4 
26 
More Than One Race 
- 
2 
- 
1 
3 
Total 
- 
34 
- 
6 
40 
 
 
1. 
REGISTRATION PROCEDURES 
 
5.1   
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified investigators.  
NCI policy requires all persons participating in any NCI-sponsored clinical trial to register and renew 
their registration annually which is done via the Registration and Credential Repository (RCR). 
 
To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and 
Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to Rave or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr). Documentation requirements per registration type are outlined in the 
table below. 
 
Documentation Required 
IVR 
(Investigator) 
NPIVR 
(Non-
physician 
Investigator) 
AP 
(Associate 
Plus) 
A 
(Associate) 
AB 
(Associate 
Basic) 
FDA Form 1572 
D 
D 
 
 
 
Financial Disclosure Form 
D 
D 
D 
 
 
NCI Biosketch (education, 
training, employment, 
license, and certification) 
D 
D 
D 
 
GCP training 
D 
D 
D 
 
 
CV (optional) 
D 
D 
D 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to participate in all CP-
CTNet clinical trials.   
 
All personnel directly involved in the performance of procedures required by the protocol and the 
collection of data should be registered in the RCR.  

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Personnel associated with the five registration types include, but is not limited to, the following: 
 
x Investigator (IVR) — MD, DO, or international equivalent 
x Non-Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD) 
x Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry access to RAVE. 
Also includes site administrator, data administrator, and consenting person. Individuals with 
an auditing role should register as an AP. 
x Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials.  
x Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems 
In addition, the site-protocol Principal Investigator (PI) must meet the following criterion: 
x 
Active registration status 
x 
The IRB number of the CIRB (IRB of record) listed on their Form FDA 1572 
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR Help 
Desk by email at RCRHelpDesk@nih.gov. 
 
6. 
NCI CENTRAL INSTITUTIONAL REVIEW BOARD 
  
The NIH policy on the Use of a Single Institutional Review Board for Multi-Site Research 
https://grants.nih.gov/grants/guide/notice-files/not-od-16-094.html became effective on January 25, 2018. 
In compliance with this policy, NCI Central IRB (NCI CIRB) is the sole IRB of record for all accruing 
sites conducting clinical trials through the CP-CTNet, all CP-CTNet  U.S.-based sites must be members 
of the NCI Central Institutional Review Board (NCI CIRB), and utilize the Cancer Prevention and 
Control  CIRB as their IRB of record. International sites should submit Research Ethics Board (REB) 
approval to the DCP Regulatory contractor following country-specific regulations. 
 
Signatory Institutions must submit a Study Specific Worksheet (SSW) to the CIRB via IRBManager to 
indicate their intent to open the study locally. The CIRB’s approval of the SSW is then communicated to 
the Principal Investigators at the Signatory Institution and the Regulatory Contractor. In order for the 
SSW approval to be processed, the Signatory Institution must inform which CIRB-approved institutions 
aligned with the Signatory Institution are participating in the study. 
 
Should changes to the study become necessary, protocol amendments will be submitted to the DCP PIO 
according to DCP Amendment Guidelines. The DCP-approved amended protocol must be approved by 
the CIRB prior to implementation. 
 
 
7. AGENT ADMINISTRATION 
 
Intervention will be administered on an outpatient basis. Reported AEs and potential risks are described in 
Section 8.2.  
 

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7.1 
Dose Regimen and Dose Groups 
 
The study is expected to have 2 dose groups. For each dosing regimen, participants will take three 60 mg 
tablets (the loading dose) on the first day of agent intervention. Participants in the first dose group will 
receive apalutamide 60 mg MWF/wk for 4-8 weeks prior to prostatectomy. Based on the PSA response, 
an additional group of participants will receive de-escalated dose at 60 mg once per week, or escalated 
dose at 60 mg daily for 4-8 weeks prior to prostatectomy. Participants may receive the agent intervention 
up to 12 weeks if the surgery is delayed. The agent intervention is not meant to delay the curative surgery. 
Only patients whose surgery is planned to allow for a minimum of 4 weeks and up to 12 weeks of agent 
intervention will be enrolled. The intervention duration will be adjusted depending on the planned surgery 
schedule. 
 
7.2 
Apalutamide Administration 
 
x 
Participant will self-administer the study agent. 
x 
Depending on the dose group, participants will take one 60 mg tablet once a day, one 60 mg 
tablet three times a week (Monday, Wednesday, Friday), or one 60 mg tablet once a week.  
x 
For each dosing regimen, participants will take three 60 mg tablets (the loading dose) on the 
first day of agent intervention. 
x 
Participants will be instructed to take the dose in the morning with or without food. 
 
7.3 
Run-in Procedures  
 
Not applicable. 
 
7.4 
Contraindications 
 
None. 
 
7.5 
Concomitant Medications 
 
Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state 
exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide) No initial dose adjustment 
is necessary, however, reduce the dose based on tolerability. 
 
Apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. 
Concomitant use of apalutamide with medications that are primarily metabolized by CYP3A4, CYP2C19, 
or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is 
recommended when possible or evaluate for loss of activity if medication is continued. Concomitant 
administration of apalutamide with medications that are substrates of UDP-glucuronosyl transferase 
(UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with 
apalutamide and evaluate for loss of activity. 
 
Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein 
(BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. At steady-state, 
apalutamide reduced the plasma exposure to fexofenadine (a P-gp substrate) and rosuvastatin (a 
BCRP/OATP1B1 substrate). Concomitant use of apalutamide with medications that are substrates of P-
gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-
gp, BCRP or OATP1B1 must be co-administered with apalutamide and evaluate for loss of activity if 
medication is continued. 

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Participants will be excluded if they are using drugs known to lower the seizure threshold, including: 
atypical antipsychotics (e.g. clozapine, olanzapine, risperidone, ziprasidone), bupropion, lithium, 
meperidine, pethidine, phenothiazine antipsychotics (e.g. chlorpromazine, mesoridazine, thioridazine),
and tricyclic antidepressants (e.g. amitriptyline, desipramine, doxepin, imipramine, maprotiline, 
mirtazapine).
Participants will also be excluded if they are using drugs in category X drug interactions with apalutamide 
(see list in Appendix E). 
All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or herbs taken 
by the participant will be documented on the concomitant medication CRF and will include: 1) start and 
stop date, dose and route of administration, and indication. Medications taken for a procedure (e.g.,
biopsy) should also be included.
7.6
Dose Modification
No dose modification will be made for Grade 1 adverse events. 
For Grade 2 adverse events definitely, probably, or possibly related to study agent persisting for more 
than 3 days, the agent dose will be held until toxicity is resolved to Grade 1 or less.
Participants with Grade 3 or 4 events that are definitely, probably, or possibly related to the study agent 
will receive no further doses and be followed for resolution of adverse events. If appropriate, they should 
remain on-study and undergo the prostatectomy.
For adverse events not considered related to study agent, the agent intervention may be continued or 
omitted at the discretion of the study physician.
7.7
Adherence/Compliance
7.7.1
Participants will be considered compliant for secondary “per protocol” statistical analysis if they 
have taken t 80% of their assigned study doses based on pill count.
7.7.2
The primary measure of medication compliance is based on pill count and supplemented with the 
Intake Calendar.  The secondary measure of compliance will be determination of plasma apalutamide
levels.
8.
PHARMACEUTICAL INFORMATION 
8.1
Apalutamide (IND #
 IND Sponsor NCI, Division of Cancer Prevention)
Apalutamide, also known as ARN-509, is a second-generation androgen receptor (AR) inhibitor that 
binds directly to the ligand-binding domain of the AR to inhibit nuclear translocation, DNA binding, and 
transcription [6]. The drug retains full antagonist activity in the setting of AR overexpression and is 
selective for AR vs. other nuclear hormone receptors [24]. In mouse xenograft models of prostate cancer, 
apalutamide administration decreased tumor cell proliferation and increased apoptosis, leading to 
decreased tumor volume [6]. Apalutamide, marketed under the brand name Erleada®, was approved by 
FDA for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic 
castration-sensitive prostate cancer (mCSPC) [12, 25].

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x 
The drug product, Erleada®, is supplied as film-coated tablets for oral administration containing 
60 mg of apalutamide drug substance. Inactive ingredients of the core tablet are colloidal 
anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose-acetate succinate, 
magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose. The 
tablets are finished with a commercially available film coating comprising the following 
excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and 
titanium dioxide. The recommended dose of apalutamide for the treatment of prostate cancer is 
240 mg (four 60 mg tablets) administered orally once daily [26]. 
 
8.2 
Reported Adverse Events and Potential Risks 
 
The safety and efficacy of apalutamide have been established in phase 3 clinical trials enrolling patients 
with mCSPC (Targeted Investigational Treatment Analysis of Novel Anti-androgen [TITAN] study 
NCT02489318) and nmCRPC (Selective Prostate Androgen Receptor Targeting with ARN-509 
[SPARTAN] study NCT01946204).  
 
The adverse events observed in each of the two trials are summarized below. Please refer to the package 
insert for more details [34]. 
 
TITAN study: This is a randomized, double-blind, placebo-controlled, multi-center clinical study, 
enrolling patients with mCSPC. Patients received either Erleada® at a dose of 240 mg daily or placebo. 
All study participants received a concomitant gonadotropin-releasing hormone (GnRH) analog or had 
prior bilateral orchiectomy. The median duration of exposure was 20 months (range: 0–34 months) in 
patients who received Erleada® and 18 months (range: 0.1–34 months) in patients who received placebo. 
Ten patients (2%) who were treated with Erleada® died from adverse reactions. The reasons for death 
were ischemic cardiovascular events (n=3), acute kidney injury (n=2), cardio-respiratory arrest (n=1), 
sudden cardiac death (n=1), respiratory failure (n=1), cerebrovascular accident (n=1), and large intestinal 
ulcer perforation (n=1). Erleada® was discontinued due to adverse reactions in 8% of patients, most 
commonly from rash (2%). Adverse reactions leading to dose interruption or reduction of Erleada® 
occurred in 23% of patients; the most frequent (>1%) were rash, fatigue, and hypertension. Serious 
adverse reactions occurred in 20% of Erleada®-treated patients and in 20% of patients receiving placebo.  
 
Additional adverse reactions of interest occurring in 2% but less than 10% of patients treated with 
Erleada® included diarrhea (9% vs. 6% on placebo), muscle spasm (3% vs. 2% on placebo), dysgeusia 
(3% vs. 1% on placebo), and hypothyroidism (4% vs. 1% on placebo). 
 
SPARTAN study: This is a randomized (2:1), double-blind, placebo-controlled, multi-center clinical 
study, enrolling patients with nmCRPC. Patients received either Erleada® at a dose of 240 mg daily or 
placebo. All patients received a concomitant GnRH analog or had a bilateral orchiectomy. The median 
duration of exposure was 16.9 months (range: 0.1–42 months) in patients who received Erleada® and 
11.2 months (range: 0.1–37 months) in patients who received placebo. Eight patients (1%) who were 
treated with Erleada® died from adverse reactions. The reasons for death were infection (n=4), myocardial 
infarction (n=3), and cerebral hemorrhage (n=1). One patient (0.3%) treated with placebo died from an 
adverse reaction of cardiopulmonary arrest (n=1). Erleada® was discontinued due to adverse reactions in 
11% of patients, most commonly from rash (3%). Adverse reactions leading to dose interruption or 
reduction of Erleada® occurred in 33% of patients; the most common (>1%) were rash, diarrhea, fatigue, 
nausea, vomiting, hypertension, and hematuria. Serious adverse reactions occurred in 25% of 
Erleada®-treated patients and in 23% of patients receiving placebo. The most frequent serious adverse 
reactions (>2%) were fracture (3%) in the Erleada® arm and urinary retention (4%) in the placebo arm. 
Additional clinically significant adverse reactions occurring in 2% or more of patients treated with 

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Erleada® included hypothyroidism (8.1% vs. 2% on placebo), pruritus (6.2% vs. 2% on placebo), and 
heart failure (2.2% vs. 1% on placebo). 
 
There were reversible breast changes in a small minority of participants in this study on the three time a 
week regimen. These participants reported enlargement of one or both breasts 1-2 months after stopping 
the study drug. The breast swelling resolved after 3-4 months of follow-up without any treatment.   
 
 
8.3  
Availability 
 
Apalutamide is manufactured by the Janssen Pharmaceutical Companies of Johnson & Johnson,  
and will be purchased by the research pharmacy at each study institution. 
 
8.4 
Agent Distribution 
The institutional research pharmacy will repackage the pills into light protected bottles with amount 
sufficient for the entire study duration based on the surgery schedule and the assigned dosing regimen 
plus an extra week of agent supply. The bottles will be dispensed to the research staff for distribution to 
the study participants or directly from research pharmacy to the study participants. Participants will be 
provided with the study drug in amount sufficient for the entire study duration based on the surgery 
schedule and the assigned dosing regimen plus an extra week of agent supply. The study drug may be 
delivered to the subject by study staff or contracted courier. Participant may also pick up the study agent 
from the clinic. If surgery is delayed, additional study drug may be delivered to the subject by study staff 
or contracted courier or picked up from the clinic by the participant.  
The study staff will review the participant’s concomitant medications to exclude those who are using the 
medications listed in Appendix E. Participants who initiate the study agent will be provided with a 
clinical trial wallet card (Appendix D) to show to their healthcare providers. Participants will be 
instructed to inform study staff prior to taking any new medications during the study. During the weekly 
contact with the participant, the coordinator will inquire if any new medications have been started and 
will remind the participant to call the study staff prior to initiating any new medications. 
 
8.5  
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of 
the inventory and disposition of all agents received from DCP. The Investigator is required to maintain 
adequate records of receipt, dispensing and final disposition of study agent. This responsibility has been 
delegated to the study site PI and the Institutional Research Pharmacy. Include on receipt record from 
whom the agent was received and to whom study agent was shipped, date, quantity and batch or lot 
number. On dispensing record, note quantities and dates study agent was dispensed to and returned by 
each participant.  
 
8.6 
Packaging and Labeling 
 
Apalutamide will be purchased from the Janssen Pharmaceutical Companies of Johnson & Johnson. The 
institutional research pharmacy will repackage the pills into light protected bottles with amount sufficient 
for the entire study duration based on the surgery schedule and the assigned dosing regimen plus an extra 
week of agent supply. The number of pills needed for each participant will be indicated on the 
prescription order. The following table summarizes how to calculate the number of pills needed for each 
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Dosing regimen 
Number of pills for agent 
intervention (A) 
Number of pills for an 
extra week of agent 
supply € 
Total number of pills to 
be filled  
60 mg QD 
3 x 60 mg tablet for day 1 + 
1 x 60 mg tablet x remaining 
projected number of agent 
intervention days 
7 x 60 mg tablet 
A + E 
60 mg MWF/wk 
5 x 60 mg tablets for week 1 
+ 3 x 60 mg tablet x projected 
remaining number of agent 
intervention weeks 
3 x 60 mg tablet 
A + E 
60 mg once/wk 
3 x 60 mg tablet for week 1 +  
1 x 60 mg tablet x projected 
remaining number of agent 
intervention weeks 
1 x 60 mg tablet 
A + E 
 
The label will contain, but not be limited to, the following information: 
x 
Protocol number 
x 
Participant study ID number  
x 
Dosing information (taking one tablet every day, taking one tablet on Monday, Wednesday, 
Friday, or taking one tablet once a week). 
x 
Expiration date  
x 
Number of tablets per container. 
 
8.7 
Storage 
 
Apalutamide tablets are supplied from the Janssen Pharmaceutical Companies of Johnson & Johnson in 
bottles of 120 tablets. Each bottle contains silica gel desiccant. The manufacturer recommends storage at 
20–25°C (68–77°F); temperature excursions are permitted to 15–30°C (59–86°F). The pharmaceutical 
partner, CP-CTNet Lead Academic Organization, the DCP agent repository contractor, DCP Medical 
Monitor, and Nurse Consultant should be notified in the event of a Temperature Excursion. 
 
8.8 
Registration/Randomization 
 
This trial will use a web-based Registration/Randomization System, developed and maintained by the CP-
CTNet Data Management, Auditing, and Coordinating Center (DMACC). The Help Desk includes 
technical personnel and administrators of the registration programs at the Data Management Center in 
Amherst, NY, USA. The Help Desk is available round the clock 7 days per week, except for New Year's 
Eve, Memorial Day, Independence Day, Thanksgiving Day, and Christmas Day. 
Frontier Science Randomization Help Desk 
4033 Maple Rd, Amherst, NY 14226 USA 
Phone: +1 716 834 0900 Extension 7301 
Email:  UserSupport_CP-CTNet@frontierscience.org 
 
Participants will be considered registered on the date they sign the approved informed consent document 
with a member of the study staff. Participants will be assigned to a dose cohort based on the sequence of 
registration. The study doesn’t involve randomization.  

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Note: The Registration and Randomization process is documented in the "Stars User Guide". 
8.9 
Blinding and Unblinding Methods 
 
Not applicable, this is an open-label study. 
 
8.10 
Agent Destruction/Disposal 
 
All unused study agents and returned study bottles will be disposed according to the institutional 
standards. 
 
9.  
CLINICAL EVALUATIONS AND PROCEDURES 
 
9.1 
Schedule of Events 
 
Evaluation/ Procedure 
Registration/Baseline 
(Visit 1)1 
Agent 
Initiation 
Agent 
Intervention2 
End-of-
Intervention1,3 
(Visit 2) 
Follow-Up 
Visit1,4 
(Visit 3) 
Extended 
Follow-Up10 
 
Informed Consent 
X 
 
 
 
 
 
Assess Eligibility 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Vital Signs/ Height and 
Weight 
X 
 
 
X5 
 
 
Baseline 
Signs/Symptoms 
X 
 
 
 
 
 
Karnofsky Performance 
Status 
X 
 
 
 
 
 
Clinical Labs 
(CBC/Diff, CMP, PSA, 
TSH, 
testosterone) 
X 
 
 
X 
X6 
 
Blood for Plasma 
Apalutamide 
X 
 
 
X 
X 
 
Request FFPE Tissue 
Slides/blocks 
 
 
 
 
X 
 
Tobacco and Alcohol 
Use Assessment 
X 
 
 
X 
 
 
Quality of Life 
Questionnaire (EPIC-
CP) 
X 
 
 
X 
 
 
COVID-19 Assessment 
X 
 
 
X 
 
 
Concomitant 
Medications 
X 
 
 
X7 
X7 
 
Dispense Study Agent8 
 
X 
 
 
 
 
Collect Study Agent 
 
 
 
X7 
X7 
 
Review Agent Intake 
Calendar 
 
 
 
X7 
X7 
 
Adverse Event (AE) 
Review 
 
 
X9 
X7 
X7 
X10 
Telephone Contact 
 
 
X9 
 
 
X10 
1 For all visits, blood draw for testosterone should occur between 7-10 AM for men < 45 years of age and prior to 2 PM for men ≥ 
45 years of age. If the schedule is not feasible at Visit 1, the blood draw may be scheduled for another day.  
2  4-8 weeks. Participants may receive the agent intervention up to 12 weeks if the surgery is delayed. Participants who are taken 
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3  Within 3 days prior to scheduled prostatectomy. In order to assess the plasma trough apalutamide levels, participants will be 
asked to hold the apalutamide dose on the day of the visit until after the blood draw. 
4  7-14 days post-prostatectomy unless encountering scheduling difficulties. This visit may be combined with the postoperative 
appointment for catheter removal. 
5  Height required at Baseline visit only. 
6 Testosterone and plasma apalutamide levels only. If testosterone remained elevated at Visit 3, a follow-up chart review will be 
conducted to capture testosterone test results if the test was repeated at the 3-month post-op standard-of-care visit. 
7  Study agent return, AE diary return, and agent intake calendar return will occur during Visit 2 if this visit occurs the day before 
surgery.  Otherwise, these will be done during post-op follow up. Collection of new Adverse Events and conmeds ends with the 
operative day.   
8  The study drug may be delivered to the subject by study staff or contracted courier. Participant may also pick up the study agent 
from the clinic. 
9   Phone contact may be substituted by text or email contact if the subject prefers. Contact will be made during the first week of 
agent intervention and then every 7-10 days for the duration of the study. Participants will be contacted prior to Visit 2 to remind 
them of the upcoming appointment and to hold that day’s dose of study agent until after their blood draw. 
10   Phone contact may be substituted by text or email contact if the subject prefers. Contact will be made 60 (± 5 days) post-
prostatectomy to capture any late onset adverse events, excluding side effects that are related to prostatectomy. 
 
9.2 
Baseline Testing/Pre-Study Evaluation 
 
At the screening/baseline visit, the informed consent form and medical records release form will be 
signed in order to obtain the biopsy/prostatectomy tissues, pathology reports and prior PSA test results. 
To minimize participant burden, remote consent may be implemented in compliance to the instructions in 
Appendix G. This visit will be scheduled between 7-10 AM, when feasible, for men < 45 years of age and 
prior to 2 PM for men ≥ 45 years of age because of circadian variation in testosterone levels. If the 
schedule is not feasible, the blood draw may be scheduled for another day. Participants will be evaluated 
for height, weight, and vital signs (temperature, pulse, and blood pressure), concomitant medications, 
medical history and baseline symptoms and signs. Baseline blood samples will be collected for CBC-diff, 
CMP, PSA, TSH, testosterone, and plasma apalutamide assay. Participants will also complete baseline 
tobacco/alcohol questionnaires and the Expanded Prostate Cancer Index Composite for Clinical Practice 
(EPIC-CP) questionnaire, and COVID-19 assessment. Subjects will be instructed on how to complete the 
Intake Calendar and Adverse Event Diary. 
 
When eligibility is confirmed from lab results, participants will be provided with the study drug in 
amount sufficient for the entire study duration based on the surgery schedule and the assigned dosing 
regimen plus an extra week of agent supply. The study drug may be delivered to the subject by study staff 
or contracted courier. Participant may also pick up the study agent from the clinic. 
 
9.3 
Evaluation During Study Intervention 
 
Participants will be contacted by phone or email during the first week of agent intervention to assess  
compliance and safety and then every 7-10 days for the duration of the study. Participants will be 
contacted prior to Visit 2 to remind them of the upcoming appointment and to hold that day’s dose of 
study agent until after their blood draw. Participants will be contacted prior to Visit 2 to remind them of 
the upcoming appointment and to hold that day’s dose of study agent until after their blood draw. 
 
9.4 
Evaluation at Completion of Study Intervention 
 
Participants will be on agent intervention based on the assigned dosing regimen for 4-8 weeks. 
Participants may continue to receive the agent intervention for up to 12 weeks if the surgery is delayed.  
 
Within 3 days prior to surgery (end-of-intervention visit), participants will return to the clinic for an end-
of-intervention blood draw for CBC-diff, CMP, PSA, TSH, and testosterone, and for plasma apalutamide 

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assay. This visit will be scheduled between 7-10 AM, when feasible, for men < 45 years of age and prior 
to 2 PM for men ≥ 45 years of age. Adverse events (AEs), concomitant medications (conmeds) and agent 
compliance will be assessed. Participants will complete the follow-up tobacco/alcohol questionnaires, 
EPIC-CP questionnaire, and COVID-19 assessment. In order to assess the plasma trough apalutamide 
levels, participants will be asked to hold the apalutamide dose on the day of the visit until after the blood 
draw. 
 
Study agent return, AE diary return, and agent intake calendar return will occur during the end-of-
intervention visit if this visit occurs the day before surgery.   
 
9.5 
Post-intervention Follow-up Period 
 
A blood sample will be collected 7-14 days post-prostatectomy to assess testosterone and plasma 
apalutamide levels. Blood draw for testosterone should occur between 7-10 AM for men < 45 years of 
age and prior to 2 PM for men ≥ 45 years of age. This visit may be combined with the postoperative 
appointment for catheter removal.  Study agent return, AE diary return, and agent intake calendar return 
will occur during this visit if not done during the end-of-intervention visit. 
 
Participants will be contacted 60 (± 5 days) days post-prostatectomy by their preferred method of contact 
to capture any late onset adverse events, excluding side effects that are related to prostatectomy (such as 
erectile dysfunction, urinary incontinence, and negative sexual side effects).  
 
At the discretion of the treating urologist, a testosterone test may be repeated at the 3-month post-surgery 
standard-of-care visit if the testosterone levels remained elevated at Visit 3. The testosterone results will 
be captured through a chart review if this was repeated at the 3-month post-op visit. 
 
Pre-intervention biopsy and post-intervention surgical pathology reports will be collected, de-identified, 
labeled with study ID and participant ID and submitted to the University of Arizona Cancer Prevention 
Clinical Trials (UA CP-CTNet) Office.  
 
Report Submission Information:  
UA CP-CTNet Office 
Attn: Frances Epstein  
1430 E. Fort Lowell, Suite 304  
Tucson, AZ 85719  
Phone: (520) 321-7798  
Fax: (520) 514-6015  
Email: UACC-CPRE@UACC.arizona.edu  
 
Unstained tissue slides (or tissue blocks) from the pre-intervention prostate biopsy and post-intervention 
prostatectomy tissue will be requested from respective pathology labs for measurement of secondary 
tissue biomarkers. 
 
9.6 
Methods for Clinical Procedures 
 
Blood specimens are collected by venipuncture with standard infectious disease precautionary procedures 
with attention to eliminating low risks to the subject including infection and bruising. 
 
 
 

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10.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
10.1 
Primary Endpoint 
 
The primary endpoint is to determine the effects of low dose apalutamide on circulating levels of Prostate 
Specific Antigen (PSA). The percent change of PSA levels from baseline to end-of-intervention will be 
determined. If the prostate biopsy was performed within 6 weeks prior to the baseline visit, the most 
recent prior PSA instead of the PSA at the baseline visit will be used for the Baseline value. The 
proportion of participants with ≥25% decline in PSA levels (from baseline to end-of-intervention) will be 
determined for each dose cohort.  
 
10.2 
Secondary Endpoints 
 
The secondary endpoints, in the order of priority, are to determine the effect of low dose apalutamide on  
x 
Reversibility of testosterone levels 7-14 days post-intervention (post-operative). The post-
operative testosterone levels will be compared with the levels at baseline and end-of-
intervention within each dose cohort.  
x 
Post-intervention plasma trough apalutamide concentrations. Post-intervention plasma trough 
apalutamide concentrations will be quantified by a sensitive and specific liquid 
chromatography-mass spectrometry assay. The correlation between plasma trough 
apalutamide and the change of PSA levels will be assessed. 
x 
Health-related quality of life (HRQOL). HRQOL will be assessed by a validated 
questionnaire (EPIC-CP) to allow for efficient and accurate measurement of urinary 
incontinence, urinary irritation, bowel, sexual, and hormonal HRQOL in prostate cancer 
patients. Changes (from baseline to end-of-intervention) in the overall score and subscore for 
each measure will be assessed for each dose group. 
10.3 
Exploratory Endpoints 
 
x 
Gleason score of pre- and post-intervention tumor(s). Changes (from most recent biopsy to 
prostatectomy) in the Gleason score of pre- and post-intervention tumor(s) will be assessed 
for each dose group. Changes in the Gleason score of pre- and post-intervention tumor(s) will 
also be assessed in a subgroup of participants where materials are available from pre- and 
post-intervention tumor(s) with matched location. It is expected that such matched materials 
will only be available in a subgroup of participants where pathology review can be performed 
on ex vivo prostate tissue sample collected at prostatectomy from the tumor(s) that MRI 
directed biopsies were collected prior to enrollment. 
x 
Intra-prostatic immune cell infiltration. CD8+, CD4+, and CD56+ positive cells in the prostate 
tissues will be assessed by immunohistochemistry. Changes (from most recent biopsy to 
prostatectomy) in these immune cells will be assessed for each dose group. Changes in 
immune cell infiltration will also be assessed in a subgroup of participants where materials 
are available from pre- and post-intervention tumor(s) with matched location.  
The effects of tobacco/alcohol use on the study endpoints will be assessed by examining the associations 
between tobacco and alcohol consumption and the effects of apalutamide on the study endpoints. 
 
 
 

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10.4 
Off-Agent Criteria  
 
Participants may stop taking study agent for the following reasons: completed the protocol-prescribed 
intervention, AE or serious adverse event (SAE), inadequate agent supply, noncompliance, concomitant 
medications, or medical contraindication. Participants will continue to be followed, if possible, for safety 
reasons and in order to collect endpoint data according to the schedule of events. A participant who is 
taken off-agent either by self or by study personnel will not be replaced by another participant. 
 
10.5 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any protocol-
required follow-up period is completed, AE/SAE, lost to follow-up, non-compliance, concomitant 
medication, medical contraindication, withdraw consent, death, determination of ineligibility (including 
screen failure).  
 
10.6 
Study Termination 
 
NCI, DCP as the study sponsor has the right to discontinue the study at any time.  
 
11. 
CORRELATIVE/SPECIAL STUDIES 
 
11.1 
Rationale for Methodology Selection 
 
Plasma trough apalutamide concentrations will be determined by a liquid chromatography-mass 
spectrometry (LC-MS) method described previously [35]. Quantification of plasma drug levels by LC-
MS provides high sensitivity, specificity, and selectivity.    
 
CD8+, CD4+, and CD56+ positive cells in the prostate tissues will be assessed by immunohistochemistry 
as described previously [17]. Immunohistochemistry is the most validated technique for measuring 
protein levels of the biomarkers of interest in formalin-fixed paraffin-embedded (FFPE) tissue. It allows 
analyses of relative expression levels of each biomarker and determination of localization of each marker. 
 
11.2 
Comparable Methods 
 
Proposed methods are standard methodologies used in published research studies. The resulting data will 
be able to be compared to existing data. 
 
12. 
SPECIMEN MANAGEMENT  
 
12.1 
Laboratories 
 
Clinical chemistry and hematology panels will be performed in an institutional or commercial diagnostic 
laboratory service (i.e., LabCorp, Sonora Quest). 
 
Quantification of plasma apalutamide levels will be performed by the University of Arizona Cancer 
Center (UACC) Analytical Chemistry Shared Resource. The tissue immunohistochemistry assays will be 
performed by the UACC Tissue Acquisition and Cellular/Molecular Analysis Shared Resource. 
 
 
 
 

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12.2 
Collection and Handling Procedures 
 
 
Blood Samples 
Clinical labs 
Baseline and End-of-Intervention Visits for CBC with differentials, CMP, PSA, TSH, and testosterone: 
Approximately 15 ml of blood (fasting or non-fasting) will be drawn to one 3-5 ml EDTA and one 7-10 
ml SST or tiger top Vacutainer tubes as directed by the clinical lab, and labeled with the subject name.   
 
Post-operative Visit for testosterone: Approximately 3 ml of blood (fasting or non-fasting) will be drawn 
to one 3-5 ml SST or tiger top Vacutainer tubes as directed by the clinical lab and labeled with the subject 
name.   
 
Samples will be processed and stored according to the standard protocol for each.  The serum tube (SST 
or tiger top) will be allowed to clot for approximately 30 minutes at room temperature then centrifuged 
for serum separation.  The EDTA tube (for CBC/diff) will be gently inverted to mix for anticoagulation.  
All samples will be stored under refrigeration prior to transfer to the commercial laboratory facility on the 
same day as obtained with a completed lab requisition. 
 
Plasma apalutamide  
Baseline, End-of-Intervention and Post-Operative Visits 
Approximately 6 ml of blood (fasting or non-fasting) will be drawn to one 6 ml EDTA Vacutainer tube.  
The EDTA tube will be gently inverted to mix for anticoagulation and then centrifuged for plasma 
separation.  Plasma will be aliquoted into 4 x 2 ml cryovials and stored at -70qC or below until analyses.  
Samples will be labeled with the study ID, subject ID, and date of collection. 
 
Prostate Tissues 
A minimum of 5 and up to 10 unstained tissue slides or tissue blocks from pre-intervention prostate 
biopsy and prostatectomy will be requested from each institution’s pathology department for 
measurement of tissue biomarkers. When available, slides or blocks from pre- and post-intervention 
tumor(s) with matched location will be requested. Tissue slides will be labeled with the study ID, subject 
ID, and date of collection. 
 
12.3 
Shipping Instructions 
 
All samples will be shipped in compliance with the International Air Transport Association (IATA) 
Dangerous Goods Regulations. Tissue slides/blocks will be shipped in batches at room temperature. 
Plasma cryovials will be shipped in batches overnight on dry ice. Tissue slides will be shipped in batches 
overnight on ice packs. Current shipper and institutional procedures must be followed.  Biologic 
specimens (Category B, UN3373) will be in leak-proof primary and secondary receptacles with puncture 
resistant packaging and absorbent material.  Shipments are to be preceded with phone/email contact to the 
receiving lab to assure the shipment will be met and processed promptly.   
 
Ship plasma samples and tissue slides/blocks to: 
 
Catherine Cordova c/o Chow Laboratory 
University of Arizona Cancer Center, Room 4971 
1515 N. Campbell Ave. 
Tucson, AZ 85724 
(520) 626-5433 
ccordova@uacc.arizona.edu  

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All samples will be shipped in compliance with the International Air Transport Association (IATA) 
Dangerous Goods Regulations. 
 
12.4 
Tissue Banking 
 
The NCI reserves the right to require the transfer of biologic specimens and data, or true copies of such 
data, acquired from research supported under this award to an eligible third party.  This transfer can occur 
in order to preserve the specimens and data and/or to continue the research.  Third parties supported under 
this award must be informed of this right   
 
13. 
REPORTING ADVERSE EVENTS  
 
DEFINITION: An adverse event (AE) means any untoward medical occurrence associated with the use of 
a drug in humans, whether or not the untoward occurrence is considered drug related. Thus, an AE can 
include any unfavorable sign (e.g., an abnormal laboratory finding), symptom, or clinical outcome 
temporally associated with the use of a test drug, active control, or placebo, regardless of whether the 
event is thought to be related to the drug. An AE can arise with the use of a drug or biologic (e.g., use for 
a purpose other than FDA-approved indication or in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose. 
 
Please note that all abnormal clinical laboratory values that are determined to be of clinical significance 
based on a physician’s assessment are to be reported as AEs. A clinically significant lab value is one that 
indicates a new disease process, an exacerbation or worsening of an existing condition, or requires further 
action(s) to be taken. Those labs determined to be of no clinical significance or of unknown clinical 
significance (per the physician’s assessment) should not be reported as AEs. Any lab value of unknown 
clinical significance should continue to be investigated/followed-up further for a final determination, if 
possible. (See the DCP Baseline and Adverse Event Reporting Guidelines 
[https://prevention.cancer.gov/clinical-trials/clinical-trials-management/cp-ctnet-instructions-forms] for 
more detail on reporting abnormal clinical laboratory values.) 
 
A list of AEs that have occurred or might occur can be found in §8.2 Reported Adverse Events and 
Potential Risks, as well as the Investigator’s Brochure or package insert.  
 
13.1 
Adverse Events 
 
13.1.1 Reportable AEs 
 
All AEs that occur after the informed consent is signed and baseline assessments are collected must be 
recorded on the AE CRF whether or not related to study agent. 
 
13.1.2 AE Data Elements: 
 
The following data elements are required for AE reporting. 
x 
AE verbatim term 
x 
NCI Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) AE term 
(MedDRA lowest level term) 
x 
CTCAE (MedDRA) System Organ Class (SOC) 
x 
Event onset date and event ended date 
x 
Treatment assignment code (TAC) at time of AE onset 
x 
Severity grade 

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x 
Attribution to study agent (relatedness) 
x 
Whether or not the event was reported as a SAE 
x 
Whether or not the participant dropped due to the event 
x 
Outcome of the event 
 
13.1.3  Severity of AEs 
 
 
 
13.1.3.1 
Identify the AE using CTCAE v5.0. The CTCAE provides descriptive terminology 
(MedDRA lowest level term) and a severity grading scale for each AE listed. A copy of the CTCAE can 
be found at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
AE severity will be assessed according to the grade associated with the CTCAE term. AEs that do not 
have a corresponding CTCAE term will be assessed according to the general guidelines for grading used 
in the CTCAE v5.0. as stated below.  
 
CTCAE v5.0 general severity guidelines:  
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL**. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE. 
   
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
13.1.4 Assessment of relationship of AE to treatment 
 
 
The possibility that the AE is related to study agent will be classified as one of the following: unrelated, 
unlikely, possible, probable, definite. Criteria for these classifications are provided in DCP’s Serious 
Adverse Event Report Form: Instructions for Completion and Submission 
(https://prevention.cancer.gov/clinical-trials/clinical-trials-management/cp-ctnet-instructions-
forms). 
  
13.1.5 Follow-up of AEs 
 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will 
be followed according to good medical practices and documented as such.  
 
 
 
 

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13.2 
Serious Adverse Events  
 
13.2.1 DEFINITION: Regulations at 21 CFR §312.32 define an SAE as any untoward medical 
occurrence that at any dose has one or more of the following outcomes: 
 
• 
Death 
• 
A life-threatening AE  
(According to FDA safety guidance, an AE is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the subject at immediate risk of death. 
It does not include an event that, had it occurred in a more severe form, might have caused 
death. Example: An allergic reaction resulting in angioedema of the larynx, allergic 
bronchospasm or anaphylaxis is considered life-threatening; however, an allergic reaction 
resulting only in a localized rash is not life-threatening.)   
     • 
In patient hospitalization or prolongation of existing hospitalization  
(NCI, DCP uses admission or stay (including emergency room) equal to or greater than 24 hours 
as the definition of hospitalization. Exceptions are hospitalization for treatment of a pre-existing 
condition [unless the condition increased in severity on study], outpatient surgery, 
planned/elective procedures, and procedures described in the protocol [e.g., pharmacokinetic 
sampling, surgery] even if the hospital stay is of the described length; however, it does include 
events resulting from any of these that fulfill other serious outcome criteria, e.g., prolongation of 
hospitalization or life-threatening.) 
• 
A persistent or significant incapacity or substantial disruption of the ability to perform normal life 
functions 
• 
A congenital anomaly or birth defect 
• 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization should also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require intervention to 
prevent one of the other outcomes. 
 
13.2.2 Reporting SAEs to DCP 
 
13.2.2.1 The LAO and all Affiliate Organizations will report SAEs on the DCP SAE Report Form as 
described in DMACC’s CP-CTNet SOP 02-01, found at  CP-CTNet SOP 02-01 Reporting Serious 
Adverse Events (cp-ctnet-dmacc.org) and DCP’s Serious Adverse Event Report Form: Instructions for 
Completion and Submission found at https://prevention.cancer.gov/clinical-trials/clinical-trials-
management/cp-ctnet-instructions-forms. 
 
13.2.2.2 Contact the DCP Medical Monitor and DCP’s Regulatory Contractor within 24 hours of 
knowledge of the event. Contact via email is preferred, but phone contact is acceptable.  
 
DCP Medical Monitor: 
Edward Sauter, MD, PhD 
National Cancer Institute, Division of Cancer Prevention 
9609 Medical Center Dr., Rm 5E326 
 
Rockville, MD 20850 
Phone: (240) 276-7657 
Cell: (240) 944-3279 
Email: edward.sauter@nih.gov 
 

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The contact information for the DCP Regulatory Contractor’s Safety Department is: phone: 650-691-4400 
x133; email: safety@ccsainc.com). 
 
Include the following information when contacting both the DCP Medical Monitor and the DCP 
Regulatory Contractor’s Safety Department: 
x 
Participant ID 
x 
Date and time of the SAE 
x 
Date and time site notified of SAE 
x 
Name of reporter 
x 
Call back phone number and email  
x 
Affiliation/Institution conducting the study 
x 
DCP protocol number 
x 
Title of protocol 
x 
Suspected drugs (if any) 
x 
Description of the SAE, including attribution to drug 
 
13.2.2.3 
The LAO and all Affiliated Organizations will email written SAE reports to the DCP 
Medical Monitor and the DCP Regulatory Contractor’s Safety Department within 48 hours of learning of 
the event using the Word SAE Report Form.    
  
13.2.2.4 
The DCP Medical Monitor and the DCP Regulatory Contractor will determine which 
SAEs require FDA submission as IND safety reports. 
 
13.2.2.5 
The LAO and all Affiliate Organizations will comply with applicable regulatory 
requirements related to reporting SAEs to the IRB/IEC.  
 
13.2.3 Follow-up of SAE 
 
Site staff should send follow-up reports as requested when additional information is available. Additional 
information should be entered on the DCP SAE Report Form in the appropriate format. Follow-up 
information should be sent to DCP as soon as available. SAE related to the study agent will be followed 
until resolved or deemed unlikely to further resolved by the Site PI, or until the subject withdraws consent 
for further follow-up. SAE unrelated or unlikely to be related to study agent will be followed for 30 days 
after the last dose of study agent or deemed unlikely to resolve by the Site PI, or until the subject 
withdraws consent for further follow-up.  
 
14. 
STUDY MONITORING 
            
14.1 
Data Management 
 
This study will report clinical data using Medidata RAVE, a cloud–based clinical trials data management 
system managed by the DMACC. RAVE will be the database of record for the protocol and subject to 
NCI and FDA audit. All RAVE users will be trained to use the system and will comply with the 
instructions in the guidelines provided to the LAO by the DMACC as well as applicable regulatory 
requirements such as 21 CFR; Part 11.  
 
14.2   Electronic Case Report Forms 
 
The System Variable and Attribute Report (SVAR) template will be used to create the study-specific 
eCRFs or SVAR workbook. DMACC will contact the LAO to determine if a meeting is needed to discuss 

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the trial and eCRFs before the DMACC creates the draft SVAR. UA CP-CTNet will use CRF templates 
from the DMACC and DCP website to develop study-specific CRFs. These templates contain NCI 
Common Data Elements (CDEs) to facilitate data collection and analysis across studies. The standard 
template set may require modification to capture the unique data elements of each protocol. NCI CDEs, 
where available, will be used for all CRF modifications. 
 
DCP will sign-off on the final SVAR workbook prior to study initiation. The SVAR workbook may 
require changes throughout the conduct of the clinical trial. The need for change may result from protocol 
amendments or other reasons. Amended SVAR workbooks and attachments will be submitted to the DCP 
Protocol Information Office.   
 
More detailed information about the SVAR development process is available at: Program Resources | CP-
CTNet DMACC website (cp-ctnet-dmacc.org) 
 
14.3 
Source Documents 
 
Source documentation for this trial will consist of protocol-specific source documents as well as selected 
clinical records (such as pathology reports and PSA laboratory values) pertinent for eligibility, medical 
history and physical findings, adverse events, and study endpoints.  Only those specific records will be 
copied for the source chart to preserve subject confidentiality. 
  
14.4 
Data and Safety Monitoring Plan 
 
The University of Arizona Cancer Center (UACC) Data and Safety Monitoring Board (DSMB) will 
provide oversight for subject safety for all UA CP-CTNet clinical trials consistent with the National 
Institutes of Health Policy for Data and Safety Monitoring dated June 10, 1998; further guidance 
statement issued by the NIH on June 5, 2000, and the policy for Data and Safety Monitoring by Data and 
Safety Monitoring Boards.  The UACC DSMB meets quarterly. 
 
Regular study-specific meetings will be used as a forum to review accrual rates, problematic issues 
relating to accrual and protocol implementation, adverse events occurrence, follow-up, and reporting; 
submission of all required study reports; and progress and outcomes of laboratory analyses. 
                                                                                                                                                                                                     
14.5 
Sponsor or FDA Monitoring  
 
The NCI, DCP (or their designee), pharmaceutical collaborator (or their designee), or FDA may 
monitor/audit various aspects of the study. These monitors will be given access to facilities, databases, 
supplies and records to review and verify data pertinent to the study.  
 
14.6 
Record Retention 
 
Clinical records for all participants, including eCRFs, all source documentation (containing evidence of 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as 
CIRB records and other regulatory documentation will be retained by the Investigator in a secure storage 
facility in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of 
Human Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidances, 
and NCI/DCP requirements, unless the standard at the site is more stringent. The records for all studies 
performed under an IND will be maintained, at a minimum, for two years after the approval of a New 
Drug Application (NDA). For NCI/DCP, records will be retained for at least three years after the 
completion of the research. NCI will be notified prior to the planned destruction of any materials. The 
records should be accessible for inspection and copying by authorized persons of the Food and Drug 

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Administration. If the study is done outside of the United States, applicable regulatory requirements for 
the specific country participating in the study also apply. 
 
14.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA) 
 
N/A 
 
15. 
STATISTICAL CONSIDERATIONS 
 
15.1 
Study Design/Description 
 
This is a Phase IIa open label dose-finding trial of low dose apalutamide in prostate cancer patients 
scheduled to undergo radical prostatectomy.  The study is expected to include 2 dose groups. Up to 20 
participants will be accrued into each dose group to initiate agent intervention. 
 
The decision of dose de-escalation/escalation will be based on the PSA response. A participant with ≥ 
25% decline in serum PSA level is considered as a responder. For participants who do not complete the 
intervention and without post-intervention PSA value, we will conservatively assume the PSA decline to 
be <25%, considered as a non-responder. 
 
Accrued participants in the first dose cohort will receive apalutamide 60 mg MWF/wk for 4-8 weeks prior 
to radical prostatectomy. Based on the PSA response, an additional cohort of participants will receive a 
de-escalated dosing regimen at 60 mg once per week, or an escalated dosing regimen at 60 mg daily for 4-
8 weeks prior to prostatectomy. To improve the efficiency of trial conduct, a continuous monitoring plan 
will be used for efficacy/futility evaluation after 12 participants have completed the dosing regimen.  
A PSA response rate of ≥50% is considered sufficient for studying the 60 mg MWF/wk and the 60 mg 
daily dose in future active surveillance studies. The posterior probabilities of observing a response rate 
≥50% are summarized below based on the observed number of responders (N_r) and a non-informative 
prior for N=12-20 evaluable participants. 
 
 
For the 60 mg MWF/wk dose, if the posterior probability is found to be ≥80% at the evaluation (with the 
first evaluation starting after 12 evaluable participants), this dose cohort will be closed for efficacy and be 
de-escalated to 60 mg once a week schedule. If the posterior probability is found to be ≤20% at the 
evaluation (with the first evaluation starting after 12 evaluable participants), this dose cohort will be 
closed for futility and be escalated to 60 mg daily dose. If the posterior probability is found to be >20% 

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and <80%, the evaluation will be repeated with one additional evaluable participant, using the same 
criteria, up to a total of 20 evaluable participants. 
 
If the regimen is escalated to 60 mg daily dose, the same probability criteria will be used to stop the dose 
cohort for efficacy or futility. 
 
For the 60 mg once a week schedule, a PSA response rate of ≥25% is considered sufficient for using this 
regimen as the starting regimen in future active surveillance studies. 
 
The posterior probabilities of observing a response rate ≥25% are summarized below based on the 
observed number of responders and a non-informative prior for 12-20 evaluable participants. 
 
 
 
Similarly, if the posterior probability is found to be ≥80% at the evaluation (with the first evaluation 
starting after 12 evaluable participants), this dose cohort will be closed for efficacy. If the posterior 
probability is found to be ≤20% at the evaluation (with the first evaluation starting after 12 evaluable 
participants), this dose cohort will be closed for futility. If the posterior probability is found to be >20% 
and <80%, the evaluation will be repeated with one additional evaluable participant, using the same 
criteria, up to a total of 20 evaluable participants. 
 
15.2 
Randomization/Stratification  
 
N/A. 
 
15.3 
Sample Size 
 
The study is expected to include 2 dose groups. Up to 20 eligible participants will be accrued into each 
dose group to initiate agent intervention. We anticipate accruing 1 participant every two months until all 
sites are activated. Once all sites are activated, we anticipate accruing 1-2 participants every month, we 
expect to complete the accrual of each dose cohort in 20 months. 
 
15.4 
Primary Objective, Endpoint(s), Analysis Plan 
 
The primary objective of this study is to determine the effects of low dose apalutamide on circulating 
levels of PSA. Percent changes in circulating levels of PSA from baseline will be measured. If the 
prostate biopsy was performed within 6 weeks prior to the baseline visit, the most recent prior PSA 

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instead of the PSA at the baseline visit will be used for the baseline value. The study is expected to have 2 
dose groups.  The dose level of the second dose cohort may be higher (escalation) or lower (de-escalation) 
than the first dose group, depending upon the PSA response in the initial cohort. Therefore, for the 
primary endpoint analysis we conservatively use Bonferroni correction while constructing the credible 
intervals for two dose groups. Specifically, the proportion of participant with ≥25% decline in PSA levels 
(from baseline to end-of-intervention) for each dose cohort will be reported along with the 97.5% credible 
interval (CI) for the response rate based on the posterior distribution of the response rate derived from a 
non-informative prior for the response rate, which is consistent with the Bayesian approach used for dose 
escalation/de-escalation. A sample size of 20 participants produces a two-sided 97.5% CI for the response 
rate with a width no wider than 0.404 (based on an observed response rate of 50%). 
Observed response rate 
Width of 97.5% CI 
5% (i.e. 1 responders) 
0.226 
10% (i.e. 2 responders) 
0.273 
15% (i.e. 3 responders) 
0.309 
20% (i.e. 4 responders) 
0.337 
25% (i.e. 5 responders) 
0.359 
30% (i.e. 6 responders) 
0.376 
35% (i.e. 7 responders) 
0.389 
40% (i.e. 8 responders) 
0.397 
45% (i.e. 9 responders) 
0.403 
50% (i.e. 10 responders) 
0.404 
55% (i.e. 11 responders) 
0.403 
 
In addition, the two-sided 97.5% credible interval (CI) for the mean percentage change in PSA for each 
dose group will be also constructed based on the posterior distribution of mean percentage change, in 
which the percentage change is assumed to follow a normal distribution and the prior distribution of the 
mean percentage change is also assumed to follow a normal distribution.  
 
15.5 
Secondary Objectives, Endpoints, Analysis Plans 
 
The secondary objectives are to assess the effects of low dose apalutamide on 1) reversibility of 
testosterone levels 7-14 days post-intervention (post-operative), 2) post-intervention plasma trough 
apalutamide concentrations, and 3) health-related quality of life (HRQOL). The exploratory objectives are 
to determine the effects of apalutamide on intra-prostatic immune cell infiltration and Gleason score and 
the effects of tobacco/alcohol use on the study endpoints. The reversibility of testosterone levels will be 
measured by the change of testosterone levels from baseline to post operation. Paired t test will be 
performed on the changes in testosterone to evaluate the effects of low dose apalutamide for each dose 
group. Pearson correlation coefficient will be derived to evaluate the correlation between the plasma 
trough apalutamide levels and the change of PSA levels. HRQOL will be assessed by EPIC-CP. Changes 
in EPIC-CP (from baseline to end-of-intervention) in the overall score and sub-score for each measure 
will be derived and paired t test will be performed to evaluate the change for each dose group. Linear 
mixed effects model with a random intercept accounting within-subject dependence will be performed to 
compare the change in Gleason score of pre- and post-intervention tumor(s) since a participant can have 
more than one tumor. Changes in the Gleason score of pre- and post-intervention tumor(s) will also be 
assessed in a subgroup of participants where materials are available from pre- and post-intervention 
tumor(s) with matched location. The intra- prostatic immune cell infiltration will be measured by CD8+, 
CD4+, and CD56+ positive cells in the prostate tissues using immunohistochemistry. Changes (from most 
recent biopsy to prostatectomy) in these immune cells will be assessed for each dose group by paired t 
test. In addition, for changes in each of the secondary/exploratory endpoints a 95% CI will be reported for 

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each of the two dose groups. To explore the effects of tobacco/alcohol use on the endpoints, linear 
regression with tobacco/alcohol use and dose level indicators as the covariates will be performed for 
percent changes in PSA and change in EPIC-CP, CD8+, CD4+, and CD56+, respectively. Linear mixed 
effects model with tobacco/alcohol use and dose level indicators as the covariates will be fitted for the 
change in Gleason score. For each of the endpoints, the interaction effect between tobacco/alcohol use 
and dose level (i.e., effect modification or heterogeneity effect) will be tested, as well. If a significant 
interaction effect is detected, then subgroup analysis will be performed by dose level and reported 
accordingly.     
Due to the exploratory nature of the secondary/exploratory endpoints, we are not planning to account for 
multiple comparisons but will interpret the findings carefully and report the total number of comparisons, 
which will then allow one to control for the false discovery rate (FDR) at a specific rate, say, ≤10% via 
the adjusted p-value method. For both primary and secondary endpoints, data will be transformed before 
performing the test (paired t test or two-sample t test) if necessary. We do not anticipate observing any 
serious adverse events based on the dose levels considered for the study. At each study dose level, 
adverse events will be tabulated by the type of adverse events along with the associated 95% confidence 
intervals. 
 
15.6 
Reporting and Exclusions 
 
All of the participants with endpoint data will be included in the primary analysis. Participants are 
considered compliant for secondary “per protocol” statistical analysis if they have taken ≥ 80% of their 
assigned study doses.  
 
15.7 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of apalutamide. Descriptive 
statistics of the type and frequency of all adverse events will be generated, including 95% confidence 
intervals. 
 
A continuous monitoring rule for safety will be instituted, to guard against excess toxicity from pre-
operative treatment with low dose apalutamide. Based on some pre-specified prior distribution for the 
unanticipated complication rate, the posterior distribution of the unanticipated complication rate will be 
derived and used to determine whether to stop the study early due to excessive complications. 
Specifically, if the probability of the 10th percentile of the posterior distribution of the unanticipated 
complication rate >5% is greater than 65% at a given time point, the study will be placed on hold to 
evaluate whether the unanticipated complications are related to apalutamide and referred to the UACC 
DSMB for evaluation of excess toxicity and recommendations on whether or not to stop the study early. We 
anticipate a low unanticipated complication rate for this study and, therefore, assume a beta distribution with 
parameters a = 5 and b = 95 (i.e. a mean complication rate of 5%) for the prior distribution. Below is a table 
summarizing the probability of the 10th percentile of the posterior probability of the unanticipated 
complication rate greater than 5% after 10 participants have been treated. If ≤ 3 participants have 
experienced any unanticipated complications, the probability that the 10th percentile of the posterior distribution > 
5% is 0%.  If 4 participants have experienced any unanticipated complications, the probability that the 10th 
percentile of the posterior distribution > 5% is 65.7%. If ≥ 5 participants have experienced any unanticipated 
complications, the probability that the 10th percentile of the posterior distribution > 5% is 100%. 
 
 
 
 
 

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Observed complication %  
(n = 10) 
Assumed complication 
rate (prior) 
5% beta(5,95) 
10% (i.e., 1 out of 10) 
0% 
20% (i.e., 2 out of 10) 
0% 
30% (i.e., 3 out of 10) 
0% 
40% (i.e., 4 out of 10) 
65.7% 
50% (i.e., 5 out of 10) 
100% 
 
15.8 
Evaluation of Response 
 
All subjects with endpoint data will be assessed for response to intervention, based on the endpoints 
described above in Sections 15.4 and 15.5. 
 
Sub-analyses may be performed on the subsets of participants, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation of 
intervention, major protocol violations, etc.).  However, sub-analyses may not serve as the basis for 
drawing conclusions concerning efficacy, and the reasons for excluding participants from the analysis 
should be clearly reported. 
 
15.9 
Interim Analysis 
 
As described above, a continuous monitoring plan will be used for efficacy/futility evaluation after 12 
participants have completed the dosing regimen and the dose cohort will be stopped early for efficacy or 
futility.  Accrual, data collection, and any adverse events will be monitored on a regular basis. 
 
15.10 Ancillary Studies 
 
None.  
 
16. 
REGULATORY AND ETHICAL CONSIDERATIONS 
 
16.1 
Required Documents 
 
Besides the regulatory information that will be entered into the Registration and Credential Repository 
(see Section 5.1), the following documents are also required: 
 
16.1.1 Documentation of Federalwide Assurance (FWA) number for the LAO and all Affiliate 
Organizations. 
 
16.1.2 Signed Investigator’s Brochure/Package Insert acknowledgement form 
 
16.1.3 Delegation of Tasks Log form for the Lead Accruing Organization and all Accruing Sites signed 
by the Principal Investigator for each site and initialed by all study personnel listed on the form.  
 
16.2 
Informed Consent 
 
All potential study participants will be given a copy of the CIRB-approved Informed Consent to review. 
The investigator will explain all aspects of the study in lay language and answer all questions regarding 

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the study. If the participant decides to participate in the study, he/she will be asked to sign and date the 
Informed Consent document. The study agent(s) will not be released to a participant who has not signed 
the Informed Consent document. Individuals who refuse to participate or who withdraw from the study 
will be treated without prejudice. 
 
Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues 
obtained during testing, operative procedures, or other standard medical practices for further research 
purposes. If applicable, statement of this option should be included within the informed consent 
document.  
 
Prior to study initiation, the informed consent document must be reviewed and approved by NCI, DCP, 
and the NCI CIRB. The NCI CIRB approves a model consent for each protocol. Each Signatory 
Institution inserts their CIRB-approved institutional boilerplate language into the model consent to create 
the CIRB-approved consent. If the model informed consent document is amended, Signatory Institutions 
must use the revised model informed consent document and insert their CIRB-approved institutional 
boilerplate language at the time the change becomes active.  
 
The NCI CIRB is the IRB of record and is the only IRB authorized to approve changes to the protocol or 
informed consent document. Institutions may require additional oversight that involves the local IRB, but 
the local IRB is not responsible for any regulatorily-required IRB actions.  
 
16.3 
Collection of Regulatory Documents 
 
Regulatory documents will be collected by the DCP regulatory contractor and reviewed for completeness 
and accuracy.  
 
16.4 
Other 
This trial will be conducted in compliance with the protocol, the International Conference on 
Harmonisation’s (ICH) Good Clinical Practice (GCP) guidelines, and the applicable regulatory 
requirements. 
17.  
ROSTER MANAGEMENT 
 
The LAO is responsible for establishing, maintaining, and monitoring all its members that participate in 
CP-CTNet studies. The LAO must have a “real-time,” comprehensive, consolidated roster of all its 
members with their relevant Cancer Therapy Evaluation Program (CTEP) institution codes, associated 
investigators, and research staff. This roster information is used for determining compliance with 
monitoring requirements 
The LAO’s organizational rosters will be managed by the CP-CTNet Roster Management 
System website (https://applications.prevention.cancer.gov/cp-ctnet). Requests to add 
memberships to a roster will be done via this website. All requests require that the 
following documents be uploaded: 
x 
Consortium Letter of Commitment
x 
Site Letter of Commitment
x 
CV/NIH Biosketch


 

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18. 
FINANCING, EXPENSES, AND/OR INSURANCE 
 
Study procedures performed during study visits will be covered by the study budget.  Research tests, 
including serum and tissue biomarker evaluations, will not be billed to the subject.  Subjects may incur 
minimal out-of-pocket expenses such as transportation but will not be charged for study agent or any 
study-related activities.  Subjects will receive monetary compensation which they may use at their 
discretion for out-of-pocket cost such as transportation.  If injury occurs, medical care will be provided 
and charged to the subject’s insurer. 
 
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21. 
McNeel DG, Smith HA, Eickhoff JC, Lang JM, Staab MJ, Wilding G, Liu G: Phase I trial of 
tremelimumab in combination with short-term androgen deprivation in patients with PSA-
recurrent prostate cancer. Cancer Immunol Immunother 2012, 61(7):1137-1147. 
22. 
Small EJ, Lance RS, Gardner TA, Karsh LI, Fong L, McCoy C, DeVries T, Sheikh NA, 
GuhaThakurta D, Chang N et al: A Randomized Phase II Trial of Sipuleucel-T with 
Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic 
Castration-Resistant Prostate Cancer. Clin Cancer Res 2015, 21(17):3862-3869. 
23. 
Madan RA, Gulley JL, Schlom J, Steinberg SM, Liewehr DJ, Dahut WL, Arlen PM: Analysis of 
overall survival in patients with nonmetastatic castration-resistant prostate cancer treated 
with vaccine, nilutamide, and combination therapy. Clin Cancer Res 2008, 14(14):4526-4531. 
24. 
de Vries R, Jacobs F, Mannens G, Snoeys J, Cuyckens F, Chien C, Ward P: Apalutamide 
Absorption, Metabolism, and Excretion in Healthy Men, and Enzyme Reaction in Human 
Hepatocytes. Drug Metab Dispos 2019, 47(5):453-464. 
25. 
Van den Bergh A, Snoeys J, De Zwart L, Ward P, Lopez-Gitlitz A, Ouellet D, Monshouwer M, 
Chien C: Pharmacokinetic Drug-Drug Interaction of Apalutamide, Part 2: Investigating 
Interaction Potential Using a Physiologically Based Pharmacokinetic Model. Clin 
Pharmacokinet 2020. 
26. 
Barratt DT, Cox HK, Menelaou A, Yeung DT, White DL, Hughes TP, Somogyi AA: CYP2C8 
Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia 
Patients. Clin Pharmacokinet 2017, 56(8):977-985. 
27. 
Tomalik-Scharte D, Fuhr U, Hellmich M, Frank D, Doroshyenko O, Jetter A, Stingl JC: Effect of 
the CYP2C8 genotype on the pharmacokinetics and pharmacodynamics of repaglinide. 
Drug Metab Dispos 2011, 39(5):927-932. 
28. 
Marcath LA, Kidwell KM, Robinson AC, Vangipuram K, Burness ML, Griggs JJ, Poznak CV, 
Schott AF, Hayes DF, Henry NL et al: Patients carrying CYP2C8*3 have shorter systemic 
paclitaxel exposure. Pharmacogenomics 2019, 20(2):95-104. 
29. 
Lai XS, Yang LP, Li XT, Liu JP, Zhou ZW, Zhou SF: Human CYP2C8: structure, substrate 

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specificity, inhibitor selectivity, inducers and polymorphisms. Curr Drug Metab 2009, 
10(9):1009-1047. 
30. 
Werk AN, Cascorbi I: Functional gene variants of CYP3A4. Clin Pharmacol Ther 2014, 
96(3):340-348. 
31. 
Sanchez Spitman AB, Moes D, Gelderblom H, Dezentje VO, Swen JJ, Guchelaar HJ: Effect of 
CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. Eur J 
Clin Pharmacol 2017, 73(12):1589-1598. 
32. 
Saiz-Rodriguez M, Almenara S, Navares-Gomez M, Ochoa D, Roman M, Zubiaur P, Koller D, 
Santos M, Mejia G, Borobia AM et al: Effect of the Most Relevant CYP3A4 and CYP3A5 
Polymorphisms on the Pharmacokinetic Parameters of 10 CYP3A Substrates. Biomedicines 
2020, 8(4). 
33. 
Bremner WJ, Vitiello MV, Prinz PN: Loss of circadian rhythmicity in blood testosterone 
levels with aging in normal men. J Clin Endocrinol Metab 1983, 56(6):1278-1281. 
34. 
Janssen Pharmaceutical Companies. ERLEADA tablets, for oral use. Full prescribing 
information. [http:///www.janssentablets.com/package-insert/product-monograph/prescribing-
information/ERLEADA-pi.pdf] 
35. 
Hallur G, Purra BR, Sulochana SP, Saini NK, Daram P, Zainuddin M, Mullangi R: Validation of 
an LC-ESI-MS/MS method for the determination of apalutamide, a novel non-steroidal 
anti-androgen in mice plasma and its application to a pharmacokinetic study in mice. J 
Pharm Biomed Anal 2018, 153:260-266. 
 
 

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APPENDIX A  PERFORMANCE STATUS CRITERIA 
 
 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
 
 

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APPENDIX B 
 
ALCOHOL AND TOBACCO QUESTIONNAIRE INSTRUCTIONS 
. 
x 
Data collection will be required for all CP-CTNet studies. 
o Data will be collected at baseline and end of every study. Data may also be collected at 
follow-up visits as determined by each protocol. If you wish to collect additional information 
beyond these core elements, you may certainly do so. However, all studies need to collect the 
basic elements in the attached eCRFs.  
o The eCRFs will be completed by the Site Staff or participant at the time of the designated 
visit. 
x 
Data will be submitted as part of the final clinical data set. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ALCOHOL ASSESSMENT-- BASELINE 
 
REGISTERING 
INSTITUTION  
 
_________________________________ 
PARTICIPANT 
ID 
 
______________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY) 
___ ___ / ___ ___ / ___ 
___ ___ ___ 
 
Instructions: 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. 
beer, a 5 oz. glass of wine, or one and a half ounces of liquor.  
When a number is requested in the response, please enter a whole number (i.e. “4”) and 
not a range or fraction of a number.  
 
1. In your entire life, have you had at least 12 drinks of any kind of alcoholic beverage?  
 
 Yes 
 No (End) 
 Refuse to answer (End) 
 Don’t know/Not sure 
 
2. In the past 12 months, on average, how often did you drink any type of alcoholic beverage?  
 
________ (Enter the number of days you drank based on the timeframe checked below.  
Enter 0 if you never drank and skip to Question 6.)  
 Week  
 Month 
 Year 
 Refuse to answer 
 Don’t know/Not sure 
 
3. In the past 12 months, on those days that you drank alcoholic beverages, on average, how 
many drinks did you have per day?  
 
________ (Enter the average number of drinks per day)  
 
 Refuse to answer 
 Don’t know/Not sure 
 
4. In the past 12 months, on how many days did you have 5 or more drinks of any alcoholic 
beverage?  
 
_________ (Enter the number of days you had 5 or more drinks or enter 0 if none.) 
 

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 Refuse to answer 
 Don’t know/Not sure 
 
5. Was there ever a time or times in your life when you drank 5 or more drinks of any kind of 
alcoholic beverage almost every day?  
 
 Yes 
 No  
 Refuse to answer 
 Don’t know/Not sure 
 
6. If you do not currently drink alcoholic beverages, but did in the past, how long has it been 
since you last drank regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago  
 Don’t know/Not sure 
 Never drank regularly 
 
7. At the heaviest point, either now or in the past, on the days when you drank, about how many 
drinks did you drink a day on the average?  
 
__________ (Enter the number of drinks a day) 
  
 Refuse to answer 
 Don’t know/Not sure 
 
8. How many years have you been drinking (or did drink) regularly?  
 
______ years 
 
 Refuse to answer 
 Don’t know/Not sure  
 
9. At what age did you begin drinking regularly?  
 
______ years of age 
 
 

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 Refuse to answer 
 Don’t know/Not sure  
 
10. What type(s) of alcohol do you drink? (Mark ALL that apply) 
 
 Wine 
 Liquor 
 Beer 
 Wine cooler 
 Other _______ (enter other type(s) of alcohol you drink) 
 
 
CRF completed by (check one):  
Study participant _____    
Study site staff      _____     Staff name (optional) ____________________________ 
Date __ __ / __ __ / __ __ __ __ 
                  (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ALCOHOL ASSESSMENT - FOLLOW-UP 
 
 
REGISTERING 
INSTITUTION  
 
_________________________________ 
PARTICIPANT ID 
 
______________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY) 
___ ___ / ___ ___ / ___ 
___ ___ ___ 
 
Instructions: 
 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. 
beer, a 5 oz. glass of wine, or one and a half ounces of liquor.  
When a number is requested in the response, please enter a whole number (i.e., “4”) and 
not a range or fraction of a number. 
 
1. During the past 30 days, did you drink any alcoholic beverages?  
 
 Yes 
 No (End) 
 Refuse to answer (End) 
 Don’t know/Not sure 
 
2. During the past 30 days, how many days per week or per month did you drink any alcoholic 
beverages, on the average?  
 
________ (Enter number of days you drank based on the timeframe checked below.  Enter 0 
if you did not drink.)  
 
 Week  
 Month 
 Refuse to answer 
 Don’t know/Not sure 
 
3. On the days when you drank, on average, about how many drinks did you have?  
 
________ (Enter the average number of drinks you had per day.) 
 
 Refuse to answer 
 Don’t know/Not sure 
 
4. In the past 30 days, on how many days did you have 5 or more drinks per day?  
 
_____________ (Enter the number of days you had 5 or more drinks or enter 0 if none.)  

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 Refuse to answer 
 Do not know/Not sure 
 
 
CRF completed by (check one):  
Study participant _____    
Study site staff      _____     Staff name (optional) ____________________________ 
Date __ __ / __ __ / __ __ __ __ 
                  (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TOBACCO ASSESSMENT – BASELINE 
 
REGISTERING 
INSTITUTION  
 
_________________________________ 
PARTICIPANT ID 
 
______________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY) 
___ ___ / ___ ___ / ___ 
___ ___ ___ 
 
Instructions:  
When a number is requested in the response, please enter a whole number (i.e. “4”) and 
not a range or fraction of a number.  
 
Section A. Basic Cigarette Use Information 
 
1. Have you smoked at least 100 cigarettes (5 packs = 100 cigarettes) in your entire life? 
 
Yes  
 
 No → Skip to Section B 
 Don’t know/Not sure → Skip to Section B 
 
2. How old were you when you first smoked a cigarette (even one or two puffs)? 
 
_______ Years old 
 
 
3. How old were you when you first began smoking cigarettes regularly?   
 
_______ Years old 
 
  Check here if you have never smoked cigarettes regularly. 
 
4. How many total years have you smoked (or did you smoke) cigarettes? Do not count any time 
you may have stayed off cigarettes. 
 
______ Years (If you smoked less than one year, write “1.”) 
 
 
5. On average when you have smoked, about how many cigarettes do you (or did you) smoke a 
day? (A pack usually has 20 cigarettes in it).  
 
_____ Number of cigarettes per day 
 
6. Do you NOW smoke cigarettes?  
 
 Everyday 
 Some days 

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 Not at all → Skip to question 8 
 
 
7.  How soon after you wake up do you smoke your first cigarette?  
 
  Within 30 minutes 
  After 30 minutes 
 
8. How long has it been since you last smoked a cigarette (even one or two puffs)?  
 
First check which one of the following choices applies to you. Then, if applicable, write a 
number on the line for how many days, weeks, months, or years it has been since your last 
cigarette. 
 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette ________ 
 Less than 1 month → Number of weeks since last cigarette _________ 
 Less than 1 year → Number of months since last cigarette __________ 
 More than 1 year → Number of years since last cigarette ___________ 
 Don’t know/Don’t remember 
 
Section B. Use of Other Forms of Tobacco 
 
9.  Have you ever used other forms of tobacco, not including cigarettes? 
  
 Yes  
 No → Skip to Section C 
 
10. How often do you/did you use other forms of tobacco?  
 
 Every day → Number of times per day ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
Year 
 
11. Which of the following products have you ever used regularly? 
 Check all that apply  
 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Waterpipe 
 Hookah 
 Clove cigarettes or kreteks 

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 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, Please specify: __________________________ 
 
12.  If you do not currently use other forms of tobacco, but did in the past, how long has it been 
since you last used other forms of tobacco regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
Section C. Second-Hand Smoke Exposure 
 
13. Are you currently living with a smoker?   
 
Yes 
 
 No  
 
14. In the past 30 days, have you lived in a place where other people smoked cigarettes indoors?  
 
Yes 
 
 No  
 
15. In the past 30 days, have you worked in a place where other people smoked cigarettes 
indoors? 
 
Yes 
 
 No  
 
16. Thinking of all your childhood and adult years, have you ever lived in a place where other 
people smoked cigarettes indoors? 
 
 
 Yes 
In total, for about how many years? _______ If less than 1, write “1.”   
 No  

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17. Thinking of all the years you have worked, have you ever worked in a place where other 
people smoked cigarettes indoors?   
 
Yes 
→ In total, for about how many years? _______ If less than 1, write “1.”    
 No 
 
 
CRF completed by (check one):  
Study participant _____    
Study site staff      _____     Staff name (optional) ____________________________ 
Date __ __ / __ __ / __ __ __ __ 
                  (MM/DD/YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TOBACCO ASSESSMENT - FOLLOW-UP 
 
REGISTERING 
INSTITUTION 
 
_________________________________ 
PARTICIPANT ID 
 
______________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY) 
___ ___ / ___ ___ / ___ 
___ ___ ___ 
 
Instructions:  
When a number is requested in the response, please enter a whole number (i.e. “4”) and 
not a range or fraction of a number.  
 
1. Do you NOW smoke cigarettes?  
 
 Everyday 
 Some days 
 Not at all → Skip to Question 3. 
 Never smoked → Skip to Question 4 
 
2. On average, when you smoked, about how many cigarettes do you (or did you) smoke a day? 
(A pack usually has 20 cigarettes in it).     
_____ Number of cigarettes per day 
 
3. How long has it been since you last smoked a cigarette (even one or two puffs)?    
 
First check which one of the following choices applies to you. Then, if applicable, write a 
whole number on the line for how many days, weeks, months, or years it has been since your 
last cigarette. 
 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette ________ 
 Less than 1 month → Number of weeks since last cigarette _________ 
 Less than 1 year → Number of months since last cigarette __________ 
 More than 1 year → Number of years since last cigarette ___________ 
 Don’t know/Don’t remember 
 
4. Since your last visit, have you used other forms of tobacco, not including cigarettes?  
 
 Yes 
  No (End) 
 
5. How often do you/did you use other forms of tobacco?  
 
 Every day → Number of times per day ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
Year 

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6. Since your last visit, which of the following products have you used?  Check all that apply 
 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Waterpipe 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, 
Specify____________________________________________________________________ 
 
7. If you do not currently use other forms of tobacco, but did in the past, how long has it been 
since you last used other forms of tobacco regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
The following instructions pertain to questions 8 - 10.  During each of the following time frames, 
please indicate whether you smoked cigarettes every day, some days, or not at all. 
 
8.  During study treatment 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable  
 
 

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9.  After the end of study treatment 
 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable (I have not completed the study treatment)  
 
10. Since your last visit to this clinic 
 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 
 
CRF completed by (check one):  
Study participant _____    
Study site staff      _____     Staff name (optional) ____________________________ 
Date __ __ / __ __ / __ __ __ __ 
                  (MM/DD/YYYY) 
 
 
 

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NATIONAL AND LOCAL RESOURCES TO HELP WITH ALCOHOL ABUSE AND 
ALCOHOLISM 
 
NIAAA’s online guide Treatment for Alcohol Problems: Finding and Getting Help is written 
for individuals, and their family and friends, who are looking for options to address alcohol 
problems. It is intended as a resource to understand what treatment choices are available and 
what to consider when selecting among them. 
https://pubs.niaaa.nih.gov/publications/treatment/treatment.htm 
Other resources: 
National Institute on Alcohol Abuse and Alcoholism www.niaaa.nih.gov  
301–443–3860  
National Institute on Drug Abuse www.nida.nih.gov  
301–443–1124  
National Clearinghouse for Alcohol and Drug Information www.samhsa.gov  
1–800–729–6686  
Substance Abuse Treatment Facility Locator www.findtreatment.samhsa.gov  
1–800–662–HELP  
Alcoholics Anonymous (AA) www.aa.org  
212–870–3400 or check your local phone directory under “Alcoholism”  
Moderation Management www.moderation.org 
212–871–0974  
Secular Organizations for Sobriety www.sossobriety.org  
323–666–4295  
SMART Recovery www.smartrecovery.org  
440–951–5357  
Women for Sobriety www.womenforsobriety.org  
215–536–8026  
Al-Anon Family Groups www.al-anon.alateen.org  
1–888–425–2666 for meetings  
Adult Children of Alcoholics  www.adultchildren.org 
310–534–1815  
 

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NATIONAL AND LOCAL RESOURCES TO HELP WITH QUITTING SMOKING 
NCI’s Smokefree.gov offers science-driven tools, information, and support that has helped 
smokers quit. You will find state and national resources, free materials, and quitting advice from 
NCI. 
Smokefree.gov was established by the Tobacco Control Research Branch of NCI, a component 
of the National Institutes of Health, in collaboration with the Centers for Disease Control and 
Prevention and other organizations. 
Publications available from the Smokefree.gov website include the following: 
x 
Clearing the Air: Quit Smoking Today for smokers interested in quitting. 
x 
Clear Horizons for smokers over age 50. 
x 
Staying Smoke-Free for Good for smokers who have recently quit. 
x 
Smoke-free for women, including pregnant women. 
x 
Smoke-free information in Spanish 
x 
Pathways to Freedom: Winning the Fight Against Tobacco for African American 
smokers. 
NCI’s Smoking Quitline at 1–877–44U–QUIT (1–877–448–7848) offers a wide range of 
services, including individualized counseling, printed information, referrals to other resources, 
and recorded messages. Smoking cessation counselors are available to answer smoking-related 
questions in English or Spanish, Monday through Friday, 8:00 a.m. to 8:00 p.m., Eastern time. 
Smoking cessation counselors are also available through LiveHelp, an online instant messaging 
service. LiveHelp is available Monday through Friday, 8:00 a.m. to 11:00 p.m., Eastern time. 
Your state has a toll-free telephone quitline. Call 1–800–QUIT–NOW (1–800–784–8669) to get 
one-on-one help with quitting, support and coping strategies, and referrals to resources and local 
cessation programs. The toll-free number routes callers to state-run quitlines, which provide free 
cessation assistance and resource information to all tobacco users in the United States. This 
initiative was created by the Department of Health and Human Services. For more information 
about quitlines, speak to an expert on the Smokefree.gov website. 
 
 
 

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APPENDIX C  
  
EXPANDED PROSTATE CANCER INDEX COMPOSITE FOR CLINICAL PRACTICE 
(EPIC-CP) 
 
 
x 
The EPIC-CP is a valid instrument that enables patient-reported health-related quality of life 
(HRQOL) to be measured efficiently and accurately in the routine clinical care of prostate cancer 
patients. The CRFs will be completed by the Site Staff or participant at the time of the designated 
visit. 
x 
Data will be submitted as part of the final clinical data set. 
 
 

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REGISTERING INSTITUTION  
_________________________________ 
PARTICIPANT ID 
______________________ 
VISIT TYPE 
__________________________ 
VISIT DATE   (MM/DD/YYYY) 
___ ___ / ___ ___ / ___ ___ ___ ___ 
 
Patients: Please answer the following questions by checking the appropriate checkbox. All questions are about your health 
and symptoms in the LAST FOUR WEEKS. Select one answer for each question. 
 
1. Overall, how much of a problem has your urinary function been for you? 
   No problem     Very small problem    Small problem     Moderate problem     Big problem            
 
2. Which of the following best describes your urinary control? 
0  Total control    1  Occasional dribbling    2  Frequent dribbling    4  No urinary control 
                        
_____ 
 
 
3. How many pads or adult diapers per day have you been using for urinary leakage? 
0  None    1  One pad per day    2  Two pads per day    4  Three or more pads per day                                       
_____ 
 
4.   How big a problem, if any, has urinary dripping or leakage been for you?  
0  No problem     1  Very small problem    2  Small problem     3  Moderate problem    4  Big problem        
_____ 
                                                                                  
Clinicians: Add the answers from questions 2-4 to calculate the Urinary Incontinence Symptom Score (out of 
12): 
         
  
5.  How big a problem, if any, has each     
                    No       Very small      Small      Moderate       Big 
      of the following been for you? 
 
 
  problem    problem     problem     problem    problem 
 
a. Pain or burning with urination………………….… 
    0          1               2  
    3           4         
_____ 
b. Weak urine stream/incomplete bladder emptying…     0          1               2  
    3           4         
_____ 
  c. Need to urinate frequently ………………………..      0          1               2  
    3           4         
_____ 
                     
Clinicians: Add the answers from questions 5a-5c to calculate the Urinary Irritation/Obstruction Symptom 
Score (out of 12):         
  
6.  How big a problem, if any, has each     
                     No       Very small      Small      Moderate      Big 
      of the following been for you? 
 
 
  problem    problem     problem     problem    problem 
 
a. Rectal pain or urgency of bowel movements……….       0          1               2  
    3           4         
_____ 
b. Increased frequency of your bowel movements…….     0          1               2  
    3           4         
_____ 
  c. Overall problems with your bowel habits…………..     0          1               2  
    3           4         
_____ 
                     
 Clinicians: Add the answers from questions 6a-6c to calculate the Bowel Symptom Score (out of 12):         
  
7.  How would you rate your ability to reach orgasm (climax)? 
 0  Very good     1  Good    2  Fair     3  Poor    4  Very poor to none                                                                
_____                                            
      
8.  How would you describe the usual quality of your erections? 

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0  Firm enough   1  Firm enough for masturbation    2  Not firm enough for    4  None at all                         
_____ 
       for intercourse          and foreplay only                                any sexual activity  
 
9. Overall, how much of a problem has your sexual function or lack of sexual function been for you? 
0  No problem     1  Very small problem    2  Small problem     3  Moderate problem    4  Big problem         
_____ 
                                                                          
Clinicians: Add the answers from questions 7-9 to calculate the Sexual Symptom Score (out of 12): 
         
  
10.  How big a problem, if any has each     
                     No       Very small      Small      Moderate      Big 
      Of the following been for you? 
 
 
  problem    problem     problem     problem    problem 
 
a. Hot flashes or breast tenderness/enlargement   
    0          1               2  
    3          4         
_____ 
(if applicable, circle either hot flashes or breast  
tenderness/enlargement to indicate which symptom you 
are experiencing. If both, circle both) 
b. Feeling depressed                                                    
    0          1               2  
    3          4         
_____ 
  c. Lack of energy                                     
  
    0          1               2  
    3          4         
_____ 
 
Clinicians: Add the answers from questions 10a-10c to calculate the Vitality/Hormonal Symptom Score (out of 
12): 
         
  
 
 
CLINICIANS: Add the five domain summary scores to calculate the Overall Prostate Cancer QOL Score out of 60:  
 
 
 
 
Investigator Signature _______________________________ 
Date 
_________________________________ 
 
 
 
 
 
 
 
 
 
 
 
(mm/dd/yyyy) 
 
 
Investigator Name (please print) 
________________________________________________________________ 
 
 
 

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APPENDIX D
PARTICIPANT CLINICAL TRIAL WALLET CARD
CLINICAL TRIAL WALLET CARD
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room.
Participant Name:  
Diagnosis/Condition:  
Study Doctor: 
Study Doctor Phone #: 
NCI Trial #:  DCP UAZ20-01-01
Study Drug(S):  Apalutamide
For more information: 1-800-4-CANCER
cancer.gov | clinicaltrials.gov

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APPENDIX E  
 
  
LIST OF DRUGS IN CATEGORY X DRUG INTERACTIONS 
 
Abemaciclib 
Alpelisib 
Antihepaciviral Combination 
Products 
Apixaban 
Apremilast 
Aprepitant 
Asunaprevir 
Avanafil 
Avapritinib 
Axitinib 
Bedaquiline 
Betrixaban 
Bortezomib 
Bosutinib 
Brigatinib 
Capmatinib 
Cariprazine 
Ceritinib 
Cobimetinib 
Copanlisib 
Crizotinib 
Dabigatran Etexilate 
Daclatasvir 
Darolutamide 
Dasabuvir 
Deflazacort 
Delamanid 
Dexlansoprazole 
Dienogest 
Doravirine 
DOXOrubicin 
Duvelisib 
Elbasvir 
Elexacaftor, Tezacaftor, and 
Ivacaftor 
Eliglustat 
Encorafenib 
Entrectinib 
Erdafitinib 
Esomeprazole 
Etravirine 
Fedratinib 
Flibanserin 
Fosaprepitant 
Fosnetupitant 
Fostamatinib 
Fostemsavir 
Gemigliptin 
Gilteritinib 
Glasdegib 
Grazoprevir 
Ibrutinib 
Idelalisib 
Indium 111 Capromab Pendetide 
Irinotecan Products 
Isavuconazonium Sulfat 
Istradefylline 
Itraconazole 
Ivabradine 
Ivacaftor 
Ivosidenib 
Ixazomib 
Lansoprazole 
Ledipasvir 
Lemborexant 
Letermovir 
Lopinavir 
Lorlatinib 
Lumacaftor and Ivacaftor 
Lumateperone 
Lumefantrine 
Lurasidone 
Lurbinectedin 
Macimorelin 
Macitentan 
Midostaurin 
MiFEPRIStone 
Naldemedine 
Naloxegol 
Neratinib 
Netupitant 
NIFEdipine 
Nilotinib 
NiMODipine 
Nintedanib 
Nisoldipine 
Olaparib 
Omeprazole 
Palbociclib 
Panobinostat 
PAZOPanib 
Pemigatinib 
Pexidartinib 
Pimavanserin 
Piperaquine 
PONATinib 
Praziquantel 
Pretomanid 
Ranolazine 
Regorafenib 
Ribociclib 
Rimegepant 
Ripretinib 
Rivaroxaban 
Roflumilast 
RomiDEPsin 
Selpercatinib 
Selumetinib 
Simeprevir 
Sofosbuvir 
Sonidegib 
SORAfenib 
Tasimelteon 
Tazemetostat 
Telithromycin 
Tezacaftor and Ivacaftor 
Ticagrelor 
Tofacitinib 
Toremifene 
Trabectedin 
Tucatinib 
Ubrogepant 
Ulipristal 
Upadacitinib 
Valbenazine 
Vandetanib 
Velpatasvir 
Venetoclax 
VinCRIStine (Liposomal) 
Vinflunine 
Vorapaxar 
Voxilaprevir 
Zanubrutinib 
 
 
 

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APPENDIX F 
 
COVID 19 ASSESSMENT INSTRUCTIONS 
. 
x 
Data collection will be required for all CP-CTNet studies. 
o Data will be collected at baseline and end of every study. All studies need to collect the 
elements in the attached eCRFs.  
o The eCRFs will be completed by the Site Staff or participant at the time of the designated 
visit. 
x 
Data will be submitted as part of the final clinical data set. 
 
 

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CP-CTNET COVID-19 BASELINE ASSESSMENT  
 
REGISTERING 
INSTITUTION  
 
_________________________________ 
PARTICIPANT 
ID 
 
______________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY) 
___ ___ / ___ ___ / ___ 
___ ___ ___ 
 
Instructions: 
The following information is being collected for all Cancer Prevention Clinical Trials 
Network (CP-CTNet) studies. Only information from before study entry should be 
reported on this form. 
 
Have you ever had a COVID-19 test?  
 Yes 
 No  
 
If Yes, have you ever received a positive test result? 
 
 Yes 
 No  
 Prefer not to answer 
 
      Date of latest positive test: _ _ /  _ _ / _ _ _ _ 
      If positive, were you symptomatic? 
 
 
 Yes 
      
 No  
 
Have you received a COVID-19 vaccine? 
 
 Yes 
 No  
 Prefer not to answer 
 
If Yes, which vaccine did you receive for your first dose? 
 
 Moderna 
 Pfizer - BioNTech  
 Johnson & Johnson 
 AstraZeneca 
 Other 
 
If Other, specify: ______________________________ 

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Date of first vaccine dose: _ _ /  _ _ / _ _ _ _ 
 
Have you received a second vaccine dose? 
 
 Yes 
 No  
 
If Yes, date of second vaccine dose:  _ _ /  _ _ / _ _ _ _ 
 
      If No, provide reason: 
 
             
 Not yet due 
 
 Second dose not required  
 
 Other 
 
If Other, specify: ______________________________ 
 
Have you received a booster dose? 
 
 Yes 
 No  
 
1. Date of first booster dose: _ _ /  _ _ / _ _ _ _ 
 
Which vaccine did you receive? 
 
 Moderna 
 Pfizer - BioNTech  
 Johnson & Johnson 
 AstraZeneca 
 Other 
 
            If Other, specify: ______________________________ 
 
2. Date of second booster dose: _ _ /  _ _ / _ _ _ _ 
 
Which vaccine did you receive? 
 
 Moderna 

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 Pfizer - BioNTech  
 Johnson & Johnson 
 AstraZeneca 
 Other 
 
            If Other, specify: ______________________________ 
 
 
Comments: 
______________________________________________________________________________
______________________________________________________________________________ 
 
 
 
 

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CP-CTNET COVID-19 FOLLOW-UP ASSESSMENT 
  
REGISTERING 
INSTITUTION  
 
_________________________________ 
PARTICIPANT 
ID 
 
______________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY) 
___ ___ / ___ ___ / ___ 
___ ___ ___ 
 
Instructions: 
The following information is being collected for all Cancer Prevention Clinical Trials 
Network (CP-CTNet) studies. Only use this form to report information that has become 
available since the last completion of a CP-CTNet COVID-19 Assessment 
 
Since your initial study visit, have you had a COVID-19 test?  
 Yes 
 No  
 
If Yes, did you receive a positive test result? 
 
 Yes 
 No  
 Prefer not to answer 
 
      Date of latest positive test: _ _ / _ _ / _ _ _ _ 
 
      If positive, were you symptomatic? 
 
 
 Yes 
      
 No  
 
Since your last study visit, have you received a COVID-19 vaccine? 
 
 Yes 
 No  
 Prefer not to answer 
 
Indicate the vaccine doses received: (Complete information below about any doses that 
were received.) 
 
 First dose only 
 Second dose only  
 Both first and second doses 
 Booster dose 
 All three doses 

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1. Date of first vaccine dose: _ _ /  _ _ / _ _ _ _ 
 
Which vaccine did you receive? 
 
 Moderna 
 Pfizer - BioNTech  
 Johnson & Johnson 
 AstraZeneca 
 Other 
 
If Other, specify: ____________________________ 
 
2. Date of second vaccine dose: _ _ /  _ _ / _ _ _ _ 
 
Which vaccine did you receive? 
 
 Moderna 
 Pfizer - BioNTech  
 Johnson & Johnson 
 AstraZeneca 
 Other 
 
If Other, specify: ____________________________ 
 
3. Date of booster dose: _ _ /  _ _ / _ _ _ _ 
 
Which vaccine did you receive? 
 
 Moderna 
 Pfizer - BioNTech  
 Johnson & Johnson 
 AstraZeneca 
 Other 
 
If Other, specify: ____________________________ 
 
4. Date of booster dose: _ _ /  _ _ / _ _ _ _ 
 
Which vaccine did you receive? 

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 Moderna 
 Pfizer - BioNTech  
 Johnson & Johnson 
 AstraZeneca 
 Other 
 
If Other, specify: ____________________________ 
 
 
Comments: 
______________________________________________________________________________
______________________________________________________________________________ 
 
 
 
 
 

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APPENDIX G 
 
REMOTE CONSENT INSTRUCTIONS 
1. The participant or their legally-authorized representative (LAR) receives a copy of the informed 
consent document (e.g., via mail, fax, email, or a web link) in advance of discussion regarding 
the study. If mailed, two copies must be mailed so the participant or LAR is able to retain a copy 
for reference when their signed document is returned to the site and they are waiting to receive 
the final copy with all necessary signatures back from the site. If an electronic-consent (e-
consent) document is provided, the content in the document must be the same as the paper-based 
consent document. 
2. The investigator or designee discusses the study with the potential participant either via telephone 
or video conferencing. The investigator/designee must have the same consent discussion via 
telephone/video conferencing that they would have had with the participant or LAR during an in-
person meeting. The investigator/designee must also implement a method to ensure the identity of 
the participant or LAR (e.g., verification of state identification or other identifying documents or 
use of personal questions or visual methods). 
3. If the potential participant or LAR agrees to participation, they sign the consent form and return it 
to the investigator (e.g., via mail, fax, email, or by signing the e-consent document). If postal mail 
is used, a pre-paid, self-addressed envelope should be provided to the participant or LAR to mail 
the signed consent form back to the investigator. The inclusion of a witness in the Remote 
Consent Procedures is dictated by local institutional policy and must follow FDA and OHRP 
requirements. When a witness is required, the research record must document the witness’ name 
and that they were present for the informed consent process. The inclusion of the witness’ 
signature on the consent form is dictated by local institutional policy. 
4. Once the research team receives the signed informed consent document from the participant or 
LAR, the investigator/designee who conducted the consent process must sign and date the 
document using the current date. Under the signature line, the investigator/designee must 
document whether consent was obtained over the telephone or video conferencing, the date of the 
telephone/video conference, and the date the signed consent was received. For 
example, “Discussed with [participant or LAR name] via [telephone or videoconferencing] 
on [insert date] and received signed consent form on [insert date].” Include a brief reason for 
performing the informed consent discussion over the telephone/videoconferencing. 
5. If the site has an informed consent policy that requires the witness to sign the consent document, 
the witness signs the informed consent. If the site does not have an informed consent policy that 
requires the signature of the witness on the consent document, then the name of the witness along 
with the date of the original consenting phone call is recorded in the research records to document 
the participation of the witness.   
6. The date the investigator/designee signs the informed consent document, not the date the consent 
discussion with the participant or LAR took place, is the official date of informed consent for the 
participant on the trial.   
7. The final informed consent document must be filed in the designated investigator/site regulatory 
file location. A copy of the final informed consent document, signed by the participant or LAR, 
the investigator, and the witness (if applicable), must be sent back to the participant via 
email/scan, fax, or postal mail. 
8. No research activities related to the study can begin until all steps of the informed consent 
process are complete.