Clinical trial NCT02770391
Conditions: Prostate Cancer
Keywords: HSD3B1 Genotype Steroid Metabolism High-risk Prostate Cancer Apalutamide ARN-509
Sponsor: Case Comprehensive Cancer Center
Start date: 2016-10-17; Completion date: 2020-04-29
Enrollment: 54 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a research study to test an investigational drug (Not FDA approved), Apalutamide given in combination with Leuprolide acetate (FDA approved) in men diagnosed with high-risk prostate cancer who have already selected to have surgery to remove their prostate gland as part of their treatment plan. The main purpose of this study is to determine how tumors make androgens (male hormones), which makes these tumors more aggressive and resistant to hormonal therapy and how a short period of treatment with Apalutamide and leuprolide acetate prior to surgery can affect the production of these hormones in normal and malignant prostate tissue.

Detailed description:
Primary Objective: To evaluate the differential effect of neo-adjuvant leuprolide and Apalutamide on dihydrotestosterone (DHT) concentration in benign prostate tissue based on HSD3B1 genotype.

Secondary Objective(s): To evaluate the differential effect of neoadjuvant leuprolide and Apalutamide on other androgen (testosterone (T), dehydroepiandrosterone (DHEA), androstenediol, 5α-androstanedione (5α-dione), androstenedione (AD), androsterone and 5α-androstanediol) concentrations in benign and malignant prostate tissue based on HSD3B1 genotype.

To compare the level of DHT, T, DHEA, androstenediol, 5α-dione, AD, androsterone and 5α-androstanediol between normal and malignant prostate tissue after neoadjuvant treatment with leuprolide and Apalutamide

To determine the safety of the combination of Leuprolide and Apalutamide administered prior to radical prostatectomy

To evaluate prostatic specific antigen (PSA), FKBP5, TMPRSS2, EZH2, H3K27 and UBE2C tissue expression (via immunohistochemistry (IHC) and quantitative polymerase chain reaction (qPCR)) in benign and malignant prostate tissue after treatment with Leuprolide and Apalutamide.

Arms: arm 1: All participating patients will receive a single dose of leuprolide 7.5 mg intramuscularly (IM) in addition to Apalutamide 240 mg orally daily for four weeks prior to radical prostatectomy (RP). Treatment will be started on day (-28) ± 3 from the scheduled RP date to minimize the variability of treatment duration. Apalutamide may be continued up to and including the day before
Interventions: intervention 1: Leuprolide acetate intervention 2: Apalutamide intervention 3: Radical prostatectomy
Intervention descriptions: intervention 1: Leuprolide acetate, Intramuscular injection - 7.5 mg, one time dose on day (-28) ± 3 intervention 2: Apalutamide, PO, 240 mg daily, starting day (-28) ± 3 until the day before radical prostatectomy. Apalutamide will be initiated the same day patients receive their leuprolide acetate injection. intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
CASE 5815 
 
 
 
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STUDY NUMBER:  CASE5815 
ClinicalTrials.gov:  NCT02770391 
IND Number:  
129702 
Protocol Date: 
July 30, 2019 
 
Sponsor: 
 
Case Comprehensive Cancer Center 
  
STUDY TITLE:  
The Association between HSD3B1 Genotype and Steroid Metabolism in Normal and 
Prostate Cancer Tissue of Men with Intermediate and High-risk Prostate Cancer 
Undergoing Radical Prostatectomy after Treatment with Apalutamide and 
Leuprolide.   
 
 
PRINCIPAL INVESTIGATOR:  
Moshe Ornstein, MD, MA 
 
 
 
 
 
 
 
 
Taussig Cancer Institute  
Cleveland Clinic  
9500 Euclid Avenue 
 
 
 
 
Cleveland, OH 44195 
216-445-6592  
 
 
 
ORNSTEM@ccf.org 
 
CO-PI: 
 
 
 
 
 
 
 
 
Nima Sharifi, MD  
 
 
 
 
Taussig Cancer Institute/Lerner Institute 
Cleveland Clinic  
9500 Euclid Avenue 
 
 
 
 
Cleveland, OH   44195 
216-445-9750  
 
 
 
Sharifn@ccf.org 


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CO- INVESTIGATORS: 
 
 
Eric A. Klein, MD 
 
 
 
Chairman 
Glickman Urological and Kidney Institute 
Cleveland Clinic 
216-444-5601 
216-636-4492 
KLEINE@ccf.org 
 
 
 
Jesse McKenney, MD 
Pathology Department 
Cleveland Clinic 
216-444-1058 
mckennj@ccf.org 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH NURSE: 
 
 
DATA MANAGER: 
Susan Taylor, RN  
Sarah Devonshire 
 
 
 
 
 
   
Taussig Cancer Institute 
Taussig Cancer Institute 
Cleveland Clinic 
Cleveland Clinic 
216-445-1690 
216-636-9521 
216-444-0114 
216-444-9302 
TAYLORS7@ccf.org 
devonss@ccf.org 
 
 
STATISTICIAN: 
 
 
STUDY COORDINATOR: 
Tomas Radivoyevitch, PhD 
Sarah Devonshire 
Taussig Cancer Institute 
Taussig Cancer Institute 
Cleveland Clinic 
Cleveland Clinic 
216-442-5649 
216-636-9521 
216-636-2498 
216-444-9302 
radivot@ccf.org 
devonss@ccf.org 
 
SUPPORT/FUNDING: 
 
Janssen Scientific Affairs, LLC 
 
 
SUPPLIED AGENT:  
 
Apalutamide (Supplied by Janssen Scientific Affairs, LLC) 
OTHER AGENT: 
 
 
LEUPROLIDE (Standard of Care) 


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SUMMARY OF CHANGES 
 
Protocol Date 
Section 
Change 
03/15/2016 
 
Initial PRMC approval 
11/15/2016 
Front page 
Version date, Remove Hamid 
 
Entire document 
Change ARN-509 to Apalutamide, footer version date 
 
4.1.2 
Added: ‘any one of the following’ and changed and to or. 
 
4.1.3 
Removed: and at least 50% tumor involvement in one of the core 
biopsies is required. 
 
6.1  
Deleted duplicate paragraph 
 
10.2.2 
Added: 1 mL purple top tube will be used for genotyping purposes at 
indicated time points. 
 
10.4 
Added: 1 10mL red top tube will be used for serum steroid studies at 
indicated time points.   
 
11 footnotes 
e: Blood will be drawn for HSD3B1 genotyping and for steroid 
metabolites for the research laboratory, anytime during the study. 
5/23/2017 
Front page 
Version Date 
 
3.1 
Changed biopsies from 3 to 1 
 
4.1.3 
Changed biopsies from 3 to 1 
12/29/2017 
Front Page 
Version date, changed statistician 
 
Table of Contents & 
throughout 
Corrected sections 
 
9.2.2 
Adverse Events of Special Interest added 
 
6.6 & 11.0 
Allow variability of timing for post-op visit to coordinate with surgical 
post-op visit.  Ideally, 4-8 weeks post-surgery.  
2/15/2018 
Front page 
Version date & Co-I removal 
 
5.2.3.3 & 11.0 
 Added labs: Direct Renin and Aldosterone/Direct Renin Ratio 
3/26/18 
5.1 & 14.1 
Added verbiage allowing any subjects that are unable to provide tissue 
samples from surgery, to be replaced, in order to obtain the target 
number of samples per cohort.  
10/30/18 
Front page 
Version Date, remove Andrew Stephenson MD, Allison Tyler & Kimberly 
Schach, add Sarah Devonshire and Pam Profusek 


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Protocol Date 
Section 
Change 
10/30/18 
1.2 
Apalutamide now listed as FDA approved for the treatment of non-
metastatic castrate resistant prostate cancer. Still investigational in this 
trial setting. 
 
5.3 
Remove name of study coordinator. Already listed on pg. 2 
 
11 
Table 2 addition of serum collection at eligibility/screening. Footnotes ‘e’ 
removed “anytime during the study” verbiage. Footnote ‘I’ added to allow 
1-3 day window for prostatectomy lab collection. 
07/30/19 
Front page 
Version Date and administrative changes throughout. Jorge Garcia 
removed as Principal Investigator and replaced with Moshe Ornstein. 
Removed Cristina Magi Galluzzi and Pam Profusek. Added Jesse 
McKenney and Susan Taylor. Remove Brian Rini. 
 
Study Schema 
Deleted study schema graphic on pg 5. Duplicate in section 3.2 
 
Protocol Summary 
Sample Size: Accrual increased to 80 patients to account for 
replacement patients and logistical restrictions. Sample size remains at 
57 patients.  
 
1.2 
Included metastatic castration sensitive prostate cancer as FDA 
approved. Updated clinical studies with Apalutamide.  
 
3.2  
Replaced graphic to include the change of ARN-509 to Apalutamide and 
post- op visit timeline 
 
4.2 
Systemic steroid therapy and herbal products deleted from exclusion 
criteria and moved to section 6.3.2.1. Hypertension permitted at provider 
discretion.  
 
5.2 
Timeline clarification: Cycle 1 Day (-28) or within 28 days  
 
6.2.1 
Dosing clarification: Subjects should take Apalutamide up to and 
including the day before radical prostatectomy 
 
6.3.2.1 
Systemic steroid therapy and herbal products added 
 
7.1 
TSH (T3 and T4) lab collection clarification 
 
9.2.2 
Adverse events of special interest for Apalutamide removed 
 
9.2.5 
SAE reporting timeline added and clarification on reporting to Sponsor 
Investigator and Janssen 
 
9.3 
For Apalutamide, package insert link provided to determine the 
expectedness of an adverse event. 
 
9.9 
SAE Fax transmission number updated 
 
11 
Study calendar updated: timeline for laboratory tests and procedures 
updated and clarified 


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Protocol Date 
Section 
Change 
 
13.1 
Updated database collection from Oncore to Forte EDC 
 
14.1 
Language updated to include new accrual increase to 80 patients to 
account for replacement patients and logistical restrictions. Sample size 
remains at 57 patients. 
 
Appendix III 
Medication Diary updated to include dosing instructions and side effects 
 
Appendix IV 
Steroid therapy and herbal products added to Prohibited medication list 


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PROTOCOL SUMMARY 
 
Protocol Number/Title 
CASE5815 
The Association Between HSD3B1 Genotype and Steroid 
Metabolism in Normal and Prostate Cancer Tissue of Men with 
Intermediate and High-risk Prostate Cancer Undergoing Radical 
Prostatectomy after a short-term treatment with Apalutamide 
and leuprolide acetate. 
Study Phase 
Phase II Study 
Brief Background/Rationale 
 
 
 
As homozygosity for HSD3B1(1245C) SNP can impact response 
and mediate resistance to androgen deprivation therapy (ADT), 
evaluating the effect of such genotype variation on the level of 
steroid metabolites and the intratumoral DHT concentration in 
benign and tumor tissue of men receiving a short course of 
Apalutamide and leuprolide acetate prior to undergo RP is of 
significant interest. We hypothesize that patients with 
homozygous HSD3B1 (1245C) inheritance that leads to a gain of 
function in 3βHSD1, will have a sustained androgen synthesis 
from extragonadal precursor steroids and higher concentrations 
of DHT compared to patients with wild-type HSD3B1 (1245A) 
inheritance in the context of testosterone suppression. In 
addition, it is expected that heterozygous HSD3B1 (1245C) 
patients will have intermediate levels of DHT. We also 
hypothesize that treatment with Apalutamide will reverse the 
effects of elevated DHT on AR signaling in benign and malignant 
prostate tissue.  For example, although DHT concentrations will 
be higher in the HSD3B1 (1245C) groups, PSA expression will 
likely be similar among all groups.  We anticipate that these 
studies will serve as the first step in identifying patients with 
localized and locally advanced prostate cancer who will benefit 
from upfront treatment with Apalutamide in addition to medical 
castration prior to undergo local definitive therapy with surgery.  
Primary Objective  
Primary Endpoint 
DHT concentration in benign prostate tissue after neo-adjuvant 
leuprolide and Apalutamide based on genotype status 
Secondary Objective(s) 
Secondary Endpoint(s) 
1. 
Other androgens (testosterone (T), 
dehydroepiandrosterone (DHEA), androstenediol, 5α-
androstanedione (5α-dione), androstenedione (AD), 


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androsterone and 5α-androstanediol) concentration in 
benign prostate tissue after neo-adjuvant leuprolide and 
Apalutamide based on genotype status 
2. 
Other androgens (DHT, T, DHEA, androstenediol, 5α-dione, 
AD, androsterone and 5α-androstanediol) concentration in 
malignant prostate tissue after neo-adjuvant leuprolide and 
Apalutamide based on genotype status. 
3. 
PSA, FKBP5, TMPRSS2, EZH2, H3K27, and UBE2C expression 
(via IHC and qPCR) in benign and malignant prostate tissue 
after neoadjuvant leuprolide and Apalutamide based on 
genotype status. 
 
Sample Size 
Based on the known frequency of the genotypes in question, 
approximately 120 male patients will be genotyped prior to 
enrollment on study. The sample size required to carry-out the 
objectives of the study will be 57 male patients. Due to logistical 
restrictions, an accrual goal of 80 male patients may be needed 
in order to capture all objectives to support this sample size. 
There won’t be any ethnic restrictions for study entry including 
during the initial genotype identification state. 
 
Disease sites/Conditions 
Prostate cancer 
Interventions 
Leuprolide acetate, Intramuscular injection - 7.5 mg, one time 
dose on day (-28) ± 3  
 
Apalutamide, PO, 240 mg daily, starting day (-28) ± 3 up to and 
including the day before radical prostatectomy. Apalutamide 
will be initiated the same day patients receive their leuprolide 
acetate injection. 
 
 
 
 
 
 
 


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ABBREVIATIONS  
 
AA  
 
abiraterone acetate 
AA/P   
abiraterone acetate plus prednisone  
AR  
 
androgen receptor 
AD  
 
androstenedione 
ADT  
 
androgen deprivation therapy 
AE 
 
adverse event  
BID 
 
bis en die (twice daily) 
5α-dione  
5α-androstanedione 
CRF 
 
case report form 
CRPC   
castration-resistant prostate cancer 
CTCAE  
Common Terminology Criteria for Adverse Events 
CYP17A1  
cytochrome P450c17 
DHEA  dehydroepiandrosterone 
DHEA-S  
dehydroepiandrosterone-sulfate 
DHT  
 
dihydrotestosterone 
DLT 
 
dose limiting toxicity 
DMFS   
distant metastasis-free survival 
HPLC   
high performance liquid chromatography 
HSD3B1  
3β-hydroxysteroid dehydrogenase-1 
HSD3B2  
3β-hydroxysteroid dehydrogenase-2 
HSD17B3  
17β-hydroxysteroid dehydrogenase type 3 
HSD17B5  
17β-hydroxysteroid dehydrogenase type 5 
LBD  
 
ligand-binding domain 
LC-MS/MS  
liquid chromatography, mass spectrometry/mass spectrometry 
MFS 
 
metastasis free survival 
OS  
 
overall survival 
PD  
 
progression of disease  
PFS  
 
progression free survival 
PSA  
 
prostate-specific antigen 
RP  
 
radical prostatectomy 
SAE 
 
serious adverse event   
SRD5A1  
steroid 5α-reductase-1 
SRA5A2  
steroid 5α-reductase-2 
T  
 
testosterone     
ULN 
 
upper limit of normal      
 


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TABLE OF CONTENTS  
  
1 
INTRODUCTION 
 
1.1 
Prostate Adenocarcinoma 
1.2 
Apalutamide 
1.3 Leuprolide Acetate 
1.4 
Androgen Metabolism 
1.5 
Preclinical Data    
1.6 
Review of Relevant Prior Clinical Trials 
1.7 
Study Rationale 
 
2 
OBJECTIVES 
2.1 
Primary 
2.2 
Secondary 
 
3 
STUDY DESIGN 
 
3.1 
Summary 
3.2 
Study schema 
 
4 
STUDY POPULATION  
 
4.1 
Inclusion criteria  
4.2 
Exclusion criteria 
4.3 
Inclusion of minorities 
  
5 
REGISTRATION   
 
6 
TREATMENT PLAN 
 
6.1 
Packaging, Storage, and Labeling 
6.2 
Dosage and administration  
6.3 
General concomitant medications and supportive care guidelines 
6.4 
Duration of therapy 
6.5 
Measures of Treatment Compliance 
6.6 
Duration of follow up 
 
 
 


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7 
DOSE DELAYS/ DOSE MODIFICATIONS 
 
Apalutamide dose adjustment in the event of toxicity 
 
8 
Pharmaceutical Information 
9 
ADVERSE EVENTS AND POTENTIAL RISKS  
 
9.1 
Management of Safety Data 
9.2 
Definitions 
9.2.1 
Adverse Events 
9.2.2 
Individual Case Safety Report (ICSR) 
9.2.3 
Product Quality Compliant (PQC) 
9.2.4 
Serious Adverse Event (SAE) 
9.3 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
9.4 
Special Reporting Situations 
9.5 
Pregnancy 
9.6 
Maintenance of Safety Information 
9.7 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints for Janssen 
9.8 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
Non-Janssen Medicinal Products 
9.9 
Transmission Methods 
9.10 Reporting Procedures for Serious Adverse Events 
9.11 Institutional Review Board Reporting Requirements 
9.12 SAE and Oncore 
9.13 Data Safety and Toxicity Committee 
9.14 Data and Safety Monitoring Plan (DSMP) 
9.15 Criteria for Defining the Severity of an Adverse Event 
9.16 End of Treatment   
   
10 PHARMACEUTICAL INFORMATION 
10.1 Tissue Procurement 
10.2 HSD3B1 Genotyping 
10.3 Immunohistochemical Staining of Cellular and Molecular Markers in Prostate Cancer 
10.4 Steroid Extraction and Measurements 
10.5 mRNA Expression 
 
 


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11 STUDY CALENDAR   
 
12 MEASUREMENT OF EFFECT 
13 RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
 
13.1 Data reporting 
13.2 Regulatory considerations 
 
14 BIOSTATISTICAL CONSIDERATIONS 
 
15 REFERENCES   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
Introduction   
1.1 Prostate Adenocarcinoma  
Prostate cancer represents 14.0% of all new cancer cases in the U.S. It is the second most common 
cause of cancer death in American males and the leading cause of cancer death in males over 85. In 
2015, it is estimated that there will be 220,800 new cases of prostate cancer and an estimated 27,540 
people will die of this disease.1 Androgen deprivation therapy (ADT), with either medical or surgical 
castration, is a critical and the most effective component of therapy for patients with metastatic or high-
risk localized prostate cancer. Normally, serum testosterone (T) is irreversibly converted to DHT in the 
prostate by steroid 5α-reductase (SRD5A). Dihydrotestosterone (DHT) is the chief endogenous agonist 
for the androgen receptor (AR) and binds and activates AR with 10-fold higher potency than T. ADT 
lowers serum T concentrations to less than 1.7 nmol/l and generates an initial tumor response in about 
90% of the patients. However, nearly all patients will eventually progress to a “castration-resistant” 
state.   
Castration-resistant prostate cancer (CRPC) is often manifested by rising levels of prostate-specific 
antigen (PSA), progressive disease on imaging studies, worsening of symptoms and ultimately death.2,3 It 
is well known that the AR continues to play a major role in disease progression in a large majority of 
cases, as demonstrated by the level of AR overexpression in castration-resistant tumor tissue and the 
level of expression of the AR regulated gene, PSA.4 In vitro growth of a metastatic prostate cancer cell 
line, LNCaP cells, maintained physiologic levels of intracellular DHT (10 nM) and proliferated despite 
castrate levels of testosterone in the media.5 Moreover, clinical studies have clearly demonstrated 
significantly higher levels of intra-tumoral androgens in CRPC from anorchid men compared with 
primary prostate tumors from untreated eugonadal men.6 As clinically demonstrated, adding a 
secondary hormonal therapy to further reduce androgen synthesis or directly inhibit AR can lead to 
declines in PSA level and disease control in CRPC. This points to the importance of intratumoral 
androgens in driving tumor progression in CRPC.7–9 Emerging evidence also demonstrates that AR can be 
activated in a ligand-independent fashion by growth factors or cytokines working independently or in 
combination.4,10 Changes in the level of ligand(s) in tumor tissue, increased levels of the protein due to 
gene amplification, activating mutations in the receptor, and changes in co-regulatory molecules are 
some of the proposed mechanisms behind the development of castration-resistant disease that are just 
beginning to unfold.11–14   
1.2 Apalutamide 
Apalutamide is an orally available, non-steroidal selective antagonist of the androgen receptor (AR). 
Apalutamide was recently FDA approved for the treatment of metastatic castration sensitive prostate 
cancer and non-metastatic castration-resistant prostate cancer, however, Apalutamide is still considered 
investigational because of its use prior to surgery. Apalutamide directly antagonizes the binding of 
androgen to the ligand-binding domain of the AR, impairing nuclear translocation and DNA binding. 
Apalutamide binds the AR with 5-fold greater affinity than the first-generation anti-androgen 
bicalutamide. Apalutamide is currently being developed for the treatment of both hormone-sensitive 
and castration-resistant prostate cancer (CRPC). 


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Clinical Studies with Apalutamide 
Study ARN-509-001 is an ongoing Phase 1/2 study in subjects with progressive CRPC. In the Phase 1 
component of the study, 30 subjects with metastatic CRPC (mCRPC) received at least 1 dose of 
Apalutamide at escalating dose levels ranging from 30 to 480 mg/day. All subjects received Apalutamide 
orally once daily, except those in the 300-, 390-, and 480-mg cohorts who received a twice-daily dosing 
regimen. There was 1 dose-limiting toxicity (DLT) observed at the 300-mg dose level (Grade 3 treatment-
related abdominal pain).26 The event lasted 6 days and resolved with dose interruption and subsequent 
dose reduction to 240 mg (120 mg twice daily). Three additional subjects were treated at the 300-mg 
dose level with no reported DLTs. No seizures were reported at any dose level. The maximum tolerated 
dose (MTD) was not determined. The pharmacokinetics (PK) profile was determined to be linear and 
dose-proportional15. The dose of 240 mg was chosen as the dose for subsequent phase III studies. 
 
Ninety-seven subjects are being evaluated in the Phase 2 portion (Cohort 1: non-metastatic [NM]-CRPC 
n=51; Cohort 2: mCRPC without previous ketoconazole, abiraterone acetate/prednisone, enzalutamide 
or chemotherapy [for mCRPC] n=25; and Cohort 3: mCRPC post abiraterone acetate/prednisone and no 
previous chemotherapy [for mCRPC] n=21). Treatment-related adverse events (AEs) in the Phase 2 
portion that have been reported to date in >10% of the subjects across the 3 cohorts included fatigue, 
diarrhea, nausea, abdominal pain, hot flush, hypothyroidism, decreased blood thyroid stimulating 
hormone, dysgeusia, decreased appetite (including weight loss), and skin rashes. In the Phase 2 portion, 
no serious adverse events (SAEs) were assessed as treatment-related. The safety profile of Apalutamide 
is consistent with the preclinical pharmacology and toxicology, and is as expected for an AR antagonist. 
 
Apalutamide demonstrated prostate-specific antigen (PSA) reductions of ≥50% at 12 weeks of 89% for 
Cohort 1, 88% for Cohort 2, and 22% for Cohort 3. Similar data were observed after 24 weeks for 
Cohorts 1 and 2. The time to PSA progression was 24 months (95% confidence interval [CI]: 16.3, NE [not 
estimable] for Cohort 1), 18 months (95% CI: 8.3, NE) for Cohort 2, and 3.7 months (95% CI: 2.8, 5.6) for 
Cohort 3. These data indicate that Apalutamide demonstrates efficacy and an acceptable safety profile 
in both NM-CRPC and mCRPC patients. 
 
Study Apalutamide-003 was a Phase 3 study of Apalutamide compared with placebo for the treatment 
of subjects with high-risk (defined as a PSA doubling time ≤10 months) NM-CRPC. Among men with 
nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic 
progression were significantly longer with apalutamide than with placebo.  Study 56021927PCR3001 
was a Phase 3 study of Apalutamide plus abiraterone acetate and prednisone compared with 
abiraterone acetate and prednisone for the treatment of subjects with chemotherapy-naïve mCRPC.  No 
clinical results are available for this study.  
 
For the most comprehensive nonclinical and clinical information as well as Reference Safety Information 
regarding Apalutamide, refer to the latest edition of the Investigator's Brochure and Addenda for 
Apalutamide. 


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1.3 
Leuprolide Acetate 
Leuprolide is an agonist of gonadotropin releasing hormone (GnRH). Acting as a potent inhibitor of 
gonadotropin secretion; continuous administration results in suppression of ovarian and testicular 
steroidogenesis due to decreased levels of LH and FSH with subsequent decrease in testosterone (male) 
and estrogen (female) levels. In males, testosterone levels are reduced to below castrate levels. 
Leuprolide may also have a direct inhibitory effect on the testes, and act by a different mechanism not 
directly related to reduction in serum testosterone.  
 
1.3.1 Clinical Use of Leuprolide in Prostate Cancer 
The objective of ADT (with any of the available GnRH  agonists- in this case Leuprolide) is to lower the 
serum testosterone level at least to the same extent as that achieved with surgical orchiectomy. 
Historically, this has correlated with a level of 1.7 nmol/L (<50 ng/dL), although contemporary laboratory 
testing indicates that testosterone levels decline to 0.7 nmol/L (<20 ng/dL) after orchiectomy. The 
potential relationship between suppression of the serum testosterone and clinical outcome is illustrated 
by a secondary analysis of the JPR.7 trial in which 626 evaluable men were treated with continuous ADT 
for a rising PSA and followed for a median of eight years [Crook J, et al. NEJM 2012; 367(10):895, Klotz L, 
et al. JCO 2015; 33(10):1151] The risk of dying was lowest in those with the greatest suppression of 
serum testosterone in the first year. Compared with a first year minimum testosterone nadir <0.7 
nmol/L, those with a nadir testosterone of 0.7 to 1.7 nmol/L had an increased risk of dying (hazard ratio 
[HR] 2.08, 95% CI 1.28-3.38), as did those a nadir >1.7 nmol/L (HR 2.93, 95% CI 0.77-4.70). Although 
timing to initiation of therapy remains controversial, ADT is the standard of care for men with advanced 
disease. ADT in combination with radiation therapy is commonly utilized in men undergoing RT as local 
definitive treatment for high-risk PCa. Similarly, ADT immediately after RP in men with positive lymph 
node disease is considered standard practice for most centers in the U.S.  
1.4 
Androgen Metabolism 
The major sites of chemical modification on the steroid backbone for DHT synthesis are carbons 3, 5 and 
17, which are modified in 3 enzymatic steps for the conversion of DHEA to DHT (Figure 1). DHEA is a 3β-
hydroxy, Δ5 steroid (double bond between carbons 5 and 6) and is enzymatically converted in CRPC 
tissues to Δ4-androstenedione (AD) by 3βHSD. 3βHSD1 and 3βHSD2 are the two human isoenzymes that 
possess this enzymatic activity.16,17 3βHSD1 is thought to be the peripherally expressed isoenzyme and 
3βHSD2 the isoenzyme in steroidogenic organs.17 However, both are detected in CRPC.6,18 We have 
previously shown that 3βHSD enzymatic activity is absolutely required for the synthesis of T and/or DHT, 
downstream AR nuclear translocation, expression of AR-responsive genes and CRPC growth.19 It was 
generally thought that AD undergoes conversion to T, which is then converted to DHT by SRD5A.20,21 
However, we have recently shown that an alternative pathway is dominant, not only in cell line models 
but also in freshly collected tumors from patients with CRPC. In this pathway, SRD5A converts AD to 5α-
androstanedione (5α-dione), which is then converted to DHT.22 Furthermore, we have shown that only 
one of two SRD5A isoenzymes, SRD5A1, is specifically required in this pathway. We have also 
demonstrated that a pitfall of pharmacologically blocking SRD5A with dutasteride is that AD is instead 


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diverted to increased synthesis of T, compensating in part for depletion of the more potent DHT22, 
resulting in modest clinical activity of SRD5A inhibition against CRPC23. 
Figure 1. Synthesis of DHEA from cholesterol in the adrenal and metabolism of DHEA to intratumoral 
androgens in CRPC. Formation of testosterone and/or dihydrotestosterone from adrenal DHEA requires 
enzymatic modification of the 3-, 5-, and 17-postions of the steroid backbone by 3βHSD, SRD5A and 17βHSD 
isoenzymes. The dominant route of dihydrotestosterone synthesis is independent of testosterone (wide green 
arrows). Dihydrotestosterone is converted to the inactive metabolites androstanediol and androsterone by 
3αHSD. De novo steroidogenesis through the “backdoor” pathway still requires 3β-hydroxyl-oxidation and Δ5-
isomerization of the cholesterol backbone by 3βHSD.   


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1.5 Preclinical Data  
Recently, a gain of function single-nucleotide polymorphism (SNP) in HSD3B1(1245C; N367T) was 
identified that can also occur as a somatic mutation in CRPC tumors.24 Germline SNP variant of 
HSD3B1(1245C, rs1047303) occurs with a reported allele frequency of 22% in general population, but 
appears to vary widely by ethnicity.25 In a group of 118 prostate cancer patients at Cleveland Clinic, the 
frequency of the variant HSD3B1(1245C) allele is 36%.26 3β-hydroxysteroid dehydrogenase isoenzyme-1 
(3βHSD1), encoded by HSD3B1, is one of the three enzymes involved in converting DHEA from the 
adrenal gland to DHT in prostate cancer tissue.22 3βHSD oxidizes 3β-hydroxyl to 3-keto and isomerizes Δ5 
to Δ4 in the process of converting DHEA to AD. These reactions together make this step practically 
irreversible by an enzyme that is required for all possible pathways that lead to the synthesis of DHT. 
Chang et al have shown that CRPC sometimes expresses the 367T form of the HSD3B1, which increases 
metabolic flux from DHEA via the 5α-dione pathway to DHT by protein resistance to ubiquitination and 
degradation rather than increased catalytic activity. This mutation increases protein half-life from 2.1 to 
27 hours which leads to a profound accumulation of 3βHSD1 with subsequent increased flux to DHT and 
ultimately increased AR activation and prostate cancer progression.24 In addition, to study the possibility 
of HSD3B1 (1245C) selection in human tumors, we sequenced matching germline and tumor DNA from 
40 men with CRPC. Among these patients, the germline of 25, 11, and 4 individuals was homozygous 
wild type HSD3B1 (1245A), heterozygous, and homozygous variant HSD3B1 (1245C), respectively. Three 
of 25 (12%) CRPC tumors with homozygous HSD3B1 (1245A) inheritance have acquired the HSD3B1 
(1245C) allele. Also, three of 11 (27%) CRPC tumors with heterozygous inheritance, have loss of 
heterozygosity (LOH) of the HSD3B1 (1245A) allele, resulting in the HSD3B1 (1245C) allele being 
predominantly detectable. In contrast, none of the 11 cases with heterozygous inheritance exhibited 
LOH of the HSD3B1(1245C) allele.24 These data support the role of the HSD3B1 (1245C) allele in the 
development of CRPC. Moreover, our review of the clinical outcomes in 118 men with prostate cancer 
who were treated with ADT for biochemical failure after prostatectomy shows that inheritance of 
HSD3B1(1245C) allele that enhances the DHT synthesis may predict resistance to ADT in prostate 
cancer.26 In this group of patients allelic frequency of HSD3B1 (1245C) was 36% with homozygous wild-
type, heterozygous, and homozygous variant detected in 37%, 53%, and 10% of the patients. We 
demonstrated that median progression free survival (PFS), distant metastasis-free survival (DMFS), and 
overall survival (OS) diminished as a function of the number of variant alleles inherited, showing a gene-
dosage effect and stepwise decrements with 0 vs. 1 vs. 2 variant alleles in all three endpoints.26   
 
1.6 Review of Relevant Prior Clinical Trials 
Based on their mechanism of action and potential utility in early stages of PCa, the use of newer agents 
like abiraterone acetate (AA) and enzalutamide in the pre-operative phase has become an attractive 
therapeutic strategy. Therefore, these agents are used in multiple studies in combination with multiple 
other agents in the neoadjuvant setting to evaluate their potential role in this setting. The clinical 
activity and safety of AA/P in the neoadjuvant setting in men undergoing RP was evaluated in two 
separate phase II studies.  The first study, a randomized phase II trial evaluated the impact of 12 weeks 
of AA/P + LHRH vs. LHRH alone in 50 high risk PCa patients (≥T1c GS ≥8, or ≥cT2b, GS≥ 7 and PSA > 


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10ng/ml).27 The second trial evaluated 24 weeks of AA given in combination with LHRh in a similar group 
of patients (n=58).28 Pathologic “tumor down-staging” and treatment effect on intra-prostatic levels of 
T, DHT and other markers of androgen biosynthesis were the main objectives of the studies. This clinical 
experience suggests that neo-adjuvant therapy with AA and LHRH is well tolerated and can lead to 
significant reduction of intra-tumoral androgen production that possibly results in tumor down-staging. 
The significance of this pathologic change remains unknown. Also, an ongoing multi-center randomized 
phase II trial is evaluating the neoadjuvant use of enzalutamide alone versus enzalutamide in 
combination with dutasteride and leuprolide in men with localized high-risk prostate cancer.29      
 
1.7 Study Rationale  
As homozygosity for HSD3B1(1245C) SNP can impact response and mediate resistance to ADT, 
evaluating the effect of such genotype variation on the level of steroid metabolites and the intratumoral 
DHT concentration in benign and tumor tissue of men receiving a short course of Apalutamide and 
leuprolide prior to undergo RP is of interest. We hypothesize that patients with homozygous HSD3B1 
(1245C) inheritance that leads to a gain of function in 3βHSD1, will have a sustained androgen synthesis 
from extragonadal precursor steroids and higher concentrations of DHT compared to wild-type HSD3B1 
(1245A) inheritance in the context of castration. Also, we expect intermediate levels of DHT in the 
heterozygous HSD3B1 (1245C) group. We also hypothesize that Apalutamide will reverse the effects of 
elevated DHT on AR signaling in prostate tissue.  For example, although DHT concentrations will be 
higher in the HSD3B1 (1245C) groups, PSA expression will be equivalent among all groups.  We 
anticipate that these studies will serve as the first step in identifying patients with prostate cancer who 
will benefit from upfront treatment with Apalutamide in addition to medical castration.   


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2 
Objectives 
2.1 Primary Objective 
To evaluate the differential effect of neo-adjuvant leuprolide and Apalutamide on 
dihydrotestosterone (DHT) concentration in benign prostate tissue based on HSD3B1 
genotype. 
 
2.2 
Secondary Objectives 
2.2.1 
To evaluate the differential effect of neoadjuvant leuprolide and Apalutamide on 
other androgen (testosterone (T), dehydroepiandrosterone (DHEA), 
androstenediol, 5α-androstanedione (5α-dione), androstenedione (AD), 
androsterone and 5α-androstanediol) concentrations in benign and malignant 
prostate tissue based on HSD3B1 genotype.  
2.2.2 
To compare the level of DHT, T, DHEA, androstenediol, 5α-dione, AD, 
androsterone and 5α-androstanediol between normal and malignant prostate tissue after 
neoadjuvant treatment with leuprolide and Apalutamide 
2.2.3 
To determine the safety of the combination of Leuprolide and Apalutamide 
administered prior to radical prostatectomy 
2.2.4 
To evaluate PSA, FKBP5, TMPRSS2, EZH2, H3K27 and UBE2C tissue expression 
(via IHC and qPCR) in benign and malignant prostate tissue after treatment 
with Leuprolide and Apalutamide and Apalutamide. 
 


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3 
Study design  
3.1 
Summary 
The primary goal of the study is to evaluate the differential effect of neo-adjuvant Apalutamide and 
leuprolide on dihydrotestosterone (DHT) concentration in benign prostate tissue based on HSD3B1 
genotype. Newly diagnosed, biopsy-proven, intermediate or high-risk prostate cancer patients (G 4+3 or 
higher, ≥T2b, PSA ≥ 10), who are candidates for radical prostatectomy (RP) are eligible to participate in 
this study. In order to have enough tumor tissue to perform all of the tests, a minimum tissue 
requirement of ≥1 positive core biopsy. All participating patients will receive a single dose of leuprolide 
7.5 mg IM in addition to Apalutamide 240 mg orally daily for four weeks prior to RP. Treatment will be 
started on day (-28) ± 3 from the scheduled RP date to minimize the variability of treatment duration. 
Apalutamide will be continued up to and including the day before radical prostatectomy. Although pre-
treatment MRIs of the prostate will be ideal, this protocol does not mandate these imaging studies for 
study enrollment. Of note, the vast majority of patients undergoing RP at our institutions undergo MRI 
of prostate for further staging purposes. Thus, the vast majority of our patients will have this completed.  
Blood will be drawn at baseline and on the day of surgery to evaluate serum PSA and androgen 
metabolite levels. After RP, fresh tissue from the surgical specimen will be sampled by the GU 
pathologist (multiple punch biopsies to increase the chance of capturing benign and tumor tissue) with 
the same methodology that we have previously described.31 All steroids will be extracted from prostate 
tissue (20 mg), derivatized by the Girard-T oxime methodology to increase sensitivity, and quantitated 
by mass spectrometry, as previously described.32  Expression of PSA transcript and protein will be 
assessed as we have performed routinely and described previously.22,24 Levels of DHT, T, DHEA, 
androstenediol, 5α-dione, AD, androsterone, and 5α-androstanediol will be measured in all specimens. 
The underlying hypothesis is that under a recessive model, homozygous HSD3B1 (1245C) is stabilizing 
and leads to a gain of function in 3βHSD1 that ultimately results in sustained androgen synthesis 
compared to wild-type HSD3B1 (1245A), after treatment with leuprolide. We expect to have 
intermediate levels of these metabolites in the heterozygous HSD3B1 (1245C) group.  


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3.2 Study Schema 
   


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4 
Study Population 
4.1 Inclusion criteria 
4.1.1 Male ≥ 18 years of age 
4.1.2 Adenocarcinoma of the prostate with histological or cytological confirmation without 
neuroendocrine differentiation or small cell histology and with any one of the following:  G 4+3 or 
higher or PSA  ≥ 10 or  ≥T2b, for whom radical prostatectomy has been recommended and who 
choose to undergo radical prostatectomy.  
4.1.3 A minimum tissue requirement of ≥1 core biopsy with tumor involvement.  
4.1.4 Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1  
4.1.5 Hemoglobin of ≥ 10 g/dL, independent of transfusion and/or growth factors within 3 months 
prior to randomization   
4.1.6 Platelet count of ≥ 100k/mL independent of transfusion and/or growth factors within 3 
months prior to randomization    
4.1.7 Serum albumin ≥3.0 g/dL    
4.1.8 Serum creatinine < 2.0 times the upper limit of normal (ULN) {or a calculated creatinine 
clearance ≥ 60 mL/min}  
4.1.9   Serum potassium ≥3.5 mmol/L  
4.1.10 Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN 
4.1.11 Total serum bilirubin levels < 1.5 x ULN (Note: In subjects with Gilbert’s syndrome, if total 
bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × ULN, 
subject may be eligible)   
4.1.12 Be capable of swallowing study agents whole as a tablet  
4.1.13 Be willing/able to adhere to the prohibitions and restrictions specified in this protocol  
4.1.14 Have signed an informed consent document indicating that the subject understands the 
purpose of and procedures required for the study and are willing to participate in the study. 
4.1.15 Medications known to lower the seizure threshold (see list under prohibited meds) must be 
discontinued or substituted at least 4 weeks prior to study entry. 
4.1.16 Agrees to use a condom (even men with vasectomies) and another effective method of birth 
control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is 
having sex with a woman who is pregnant while on study drug and for 3 months following the last 
dose of study drug. Must also agree not to donate sperm during the study and for 3 months following 
the last dose of study drug.     
 


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4.2 Exclusion criteria  
Potential subjects who meet any of the following criteria will be excluded from participating in the 
study.  
4.2.1 The use of any prior hormones including LHRH agonists, LHRH antagonists, antiandrogens 
such as bicalutamide, flutamide and nilutamide, and/or the use of 5-alpha reductase inhibitors, PC- 
SPES (or PC-x product), Megestrol Acetate, or estrogen containing nutriceuticals within 6 months of 
study treatment initiation.  
4.2.2 Prior radiation therapy, immunotherapy, chemotherapy or other investigational therapy 
given for prostate cancer. 
4.2.3 "Currently active" second malignancy other than non-melanoma skin cancers or non-muscle 
invasive transitional cell carcinoma of bladder. Patients are not considered to have a "currently 
active" malignancy if they have completed therapy and are now considered (by their physician) to be 
at less than 30% risk for relapse. 
4.2.4 History of seizure or 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 randomization, 
brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas 
that are causing edema or mass effect) 
4.2.5 Have received treatment with any form of therapy with CYP17 inhibitory activity such as 
ketoconazole, aminoglutethemide, or an antiandrogen such as bicalutamide within 6 months of study 
treatment initiation.  
4.2.6 Systemic corticosteroids within 6 months of enrollment 
4.2.7 Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis)  
4.2.8 Have uncontrolled hypertension; subjects with a history of hypertension are permitted in the 
study provided their blood pressure is controlled by anti-hypertensive therapy, at the discretion of 
the treating physician.  
4.2.9 Have a known history of pituitary or adrenal dysfunction  
4.2.10 Have clinically significant heart disease as evidenced by severe or unstable angina, 
myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic 


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events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or 
clinically significant ventricular arrhythmias within 6 months prior to randomization  
4.2.11 Have a history of gastric bypass surgery or severe malabsorption that may interfere with the 
absorption of the study agents  
4.2.12 Be taking or require the use of prohibited medications as listed in Section 6.3.2.1  
4.2.13 Have any condition that, in the opinion of the investigator, would compromise the well-being 
of the subject or the study or prevent the subject from meeting or performing study requirements  
4.3 Inclusion of Minorities 
Men of all races and ethnic groups, English or non-English-speaking are eligible for this trial. 
5 
Registration 
5.1 General Guidelines 
All subjects who have been consented are to be registered in the OnCore Database. Eligible patients will 
be entered on study centrally at the Cleveland Clinic Taussig Cancer Institute by the Study Coordinator. 
Following 
registration, 
patients 
should 
begin 
protocol 
treatment 
on                             
day (-28) ± 3 days  which is set based on the scheduled surgery date. If a patient does not receive protocol 
therapy as scheduled following registration, the patient’s registration on the study may be canceled. For 
those subjects who are consented, but not enrolled, the reason for exclusion must be recorded. The Study 
Coordinator should be notified of cancellations as soon as possible. 
A subject who e i t h e r  prematurely discontinues from the study before completing 
28 days of the treatment, prior to surgery, or for whom we are unable to obtain a tissue sample from, 
may be replaced at the discretion of the PI.  


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5.2 Pre-treatment Evaluation  
Clinical: required on Cycle 1 Day (-28) or within 28 days before the treatment initiation   
5.2.1 
History and physical examination, including height, weight, and vital signs 
5.2.2 
Performance status evaluation 
5.2.3 
Laboratory /Diagnostic: required within 28 days before the treatment initiation. 
5.2.3.1 
CBC, platelet count and differential 
5.2.3.2 
Serum chemistries: includes BUN, Creatinine, ALT, and AST, glucose, alkaline 
phosphatase, total bilirubin, TSH and LDH. If TSH is abnormal a T3 and T4 level will 
be required. 
5.2.3.3 
Testosterone, DHEA, DHEA-S, and AD, Direct Renin and Aldosterone/Direct Renin 
Ratio serum level  
5.2.3.4 
PSA 
5.2.3.5 
Study blood draw for the measurement of serum steroids concentration   
5.2.3.6 
Imaging/Diagnostic: will be performed at the discretion of the treating physician. 
Obtaining prostate MRI is preferred but not mandatory for the study enrollment.  
5.3 Registration process 
To register a patient, the following documents should be completed by the research nurse and e-mailed 
to the Study Coordinator: 
 
Registration Form  
 
Eligibility Worksheet  
 
Copy of source documentation (required laboratory tests, radiographic scans (if applicable), 
physician notes, nursing notes, list of medications, pathology/surgical reports, etc.) 
Signed patient consent form to complete the registration process, the Coordinator will 
 
Verify patient eligibility worksheet is complete 
 
Request additional documentation if necessary 
 
Assign a patient study number 
 
Register the patient on the study using the ONCORE database 
6 
E-mail a letter of Confirmation of Registration, including the patient study number, to the   
responsible research nurse treatment plan. 
 
    


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6.1 Packaging, Storage, and Labeling 
 
Apalutamide will be supplied as 60mg tablets packaged in 30-ct, 120 cc HDPE bottles with child-
resistant closures and tamper proof heat induction seals. At the clinical and at the patient’s home, 
the study drug should be stored at room temperature and protected from head; do not freeze. 
Each bottle of study drug will be labeled with the required regulatory agency warning statement, 
the protocol number, and directions for patient use and storage. The Investigator will ensure that 
the study drug is stored in appropriate conditions in a secure location with controlled access. 
6.2 Dosage and Administration 
6.2.1 Description of Study agents and Administration 
Study agents include Apalutamide and leuprolide. Apalutamide will be provided by the study. Subjects 
are to receive the following:  
 
Leuprolide 7.5 mg IM x 1 dose on day (-28) ± 3 days 
 
Apalutamide 240 mg (4 x 60 mg tablets) by mouth [PO] on a continuous once-daily dosing 
regimen.  
Sufficient study medication for an entire treatment course till the day of surgery will be distributed on 
the first day of treatment. Apalutamide will be self-administered on an outpatient basis during the 
study, once daily, with or without food. Treatment will start on Day (-28) ± 3 days from the scheduled 
date for radical prostatectomy. Subjects may take Apalutamide up to and including the day before 
radical prostatectomy, at which time the medication will be discontinued.  
It is anticipated that individual patients may occasionally forget to take a dose. In those cases, missed 
doses should only be replaced if the patient remembers within a 12-hour window. After that, patients 
should just take the next dose the following day, without compensating for the missed dose. 
 


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6.3 General Concomitant Medication and Supportive Guidelines 
6.3.1 Pre-study therapy 
To be eligible for this study, subjects must have a new diagnosis of prostate cancer with no history of 
previous treatments for prostate cancer. 
6.3.2 Concomitant therapy 
All patients should be maintained on the same medications throughout the entire study period, as 
medically feasible, with minimum introduction of new chronic therapies. Standard medical treatment as 
applicable is allowed except for treatments noted in the exclusion criteria and/or listed in the prohibited 
medications section below. 
6.3.2.1 Prohibited medications and treatments 
As a class effect, androgen receptor antagonists have been associated with seizures due to an off-
target mechanism of action (GABAA inhibition).33,34    
To date, no patients receiving Apalutamide have experienced seizures, however, in preclinical 
experiments, at very high doses, dogs treated with Apalutamide had tremors and generalized 
seizures. Patients will be closely monitored for seizures, but as a precautionary measure, drugs 
known to decrease the seizure threshold and/or cause seizure will be prohibited while on study. A 
list of the medications which are PROHIBITED while on study: 
 
Aminophylline/theophylline 
 
Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone) 
 
Bupropion  
 
Lithium  
 
Meperidine and pethidine  
 
Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine)  
 
Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, 
imipramine, maprotiline, mirtazapine)  
 
Herbal products that may have hormonal anti-prostate cancer activity and/or are known 
to decrease PSA levels (e.g. saw palmetto). All herbal supplements must be discussed 
with the study provider and discontinued at the provider’s discretion.   
 Current systemic steroid or corticosteroid therapy (inhaled or topical steroids are 
also not allowed), unless waived at the provider’s discretion. 
 
[Please see the appendix IV for a more comprehensive list (with brand names)]   
6.3.2.2 Restricted Concomitant Medications  
 
Apalutamide is metabolized primarily by human CYP3A4, thus co-administration with strong 
inhibitors or inducers of CYP3A4 should be avoided as much as possible. Apalutamide may also 
induce CYP3A4; therefore, caution should be taken when administered in conjunction with 
CYP3A4 substrates that have a narrow therapeutic index. Examples of the strong CYP3A4 
inhibitors and inducers include the following: 


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o Strong CYP3A4 inhibitors: itraconazole, clarithromycin, erythromycin, diltiazem, 
verapamil, delavirdine, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, voriconazole, grapefruit juice (or grapefruits); co-administration with any of 
these agents may increase Apalutamide plasma concentrations 
o  Strong CYP inducers: phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, efavirenz, tipranivir, St. John's wort; co-administration with any of these 
agents may decrease Apalutamide plasma concentrations 
 
Apalutamide may also induce CYP3A4; therefore, caution should be taken when administered 
in conjunction with CYP3A4 substrates that have a narrow therapeutic index 
 
The potential for drug-drug interaction between Apalutamide and warfarin (e.g., Coumadin) is 
unknown at present. If a patient is taking Coumadin, re-assess PT/INR as clinically indicated and 
adjust the dose of Coumadin accordingly. 
 
Corticosteroids: due to possible resistance mechanisms which may be contributed by 
glucocorticoid receptor signaling, concurrent use of corticosteroids during the study is not 
recommended.  
 
Avoid grapefruit and pomegranate juice and/or fruits  
6.3.3 Life style guidelines 
Patients of childbearing potential must agree to practice some form of effective contraception, such as 
vasectomy, double barrier contraception, or sexual abstinence prior to entering into the study and for 6 
months following the last dose of study drug. 
There are no dietary restrictions with the exception of grapefruit and pomegranate fruits and/or juice 
while the patient is on study. Study treatment can be taken with or without food. 
6.4 Duration of Therapy 
All patients will be treated with one dose of leuprolide given IM on day (-28) ± 3 days followed by 
Apalutamide starting on day (-28) ± 3 days from the date of RP. The treatment will start on Day (-28) ± 3 
days which is set based on the scheduled date of RP and will be continued till the day of surgery.  
 
6.5 Measures of Treatment Compliance  
All patients will complete a daily diary documenting the intake of Apalutamide 
At post-op follow up visit, patients will be asked to return any remaining study drug as well as all used 
and unused study drug containers.  
Treatment compliance will be defined as the number of tablets taken divided by the expected number 
of tablets and reported as percentage. In case of dose reductions, the expected number of tablets 
should reflect the new dose level.  
Tablets that are not returned will be considered to have been taken, unless otherwise specified in the 
case report form (CRF). 


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6.6 
Duration of Follow up 
All patients will be evaluated within 4-8 weeks after RP to rule out any potential AEs after 
discontinuation of the treatment. Any clinically significant abnormalities persisting at the end of the 
study will be followed by the investigator until resolution or until a clinically stable endpoint is reached. 
If patient has no AEs with regards to study agents this will be the last study related follow up.  
7 
Dose Delays/ Dose Modifications  
7.1 
Safety Monitoring 
Thyroid stimulating hormone (TSH) should be evaluated throughout the study (with T3 and T4 done only 
if TSH is abnormal) as follows: 
• 
Cycle 1, Day (-28) or within 28 days before treatment initiation   
• 
Pre-Op Evaluation 
• 
Follow Up Visit 
 
7.2 
Apalutamide Dose Modifications in the Event of Toxicity 
 
Dose interruptions and/or reductions for each patient will be permitted provided that study 
discontinuation criteria have not been met (please see Section 9.16 End of Treatment). 
 
Patients experiencing Grade 3 treatment-related adverse events will have study drug held 
until the severity of the toxicity decreases to Grade 1 or returns to baseline. If improvement 
occurs within 7 days, dosing may be restarted at the next level dose reduction.  Exception to 
hold includes clinically insignificant lab abnormalities and hypertension, as deemed by the 
treating physician.  Events that can be mitigated with optimal treatment within 2 days of the 
occurrence do not require a dose reduction; dose may resume at previous level.  
 
Any patient experiencing a drug related Grade 4 toxicity of any duration will be permanently 
discontinued.  
 
Patients experiencing treatment-related seizure of any grade or grade (G) 4 neurotoxicity 
will have study drug permanently discontinued. 
 
At any given dose level, if patients experience gastrointestinal (GI) discomfort due to the 
number of tablets, they will be allowed to switch to a BID regimen as needed. 
 
A maximum of one dose level reduction will be allowed.  
Any patient requiring Apalutamide treatment interruption longer than 7 days during the 
treatment period will meet the criteria for end of study treatment and study 
discontinuation. 
 
 
 
 
 
 


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Table 1.   Apalutamide Dose Levels 
Toxicity 
Dose of Apalutamide (assuming 240 mg/day 
dosing) 
Grade 1 or 2 
No change 
≥Grade 3 or higher 
Hold until Grade 1 or baseline, resume at full 
dose 
First Recurrence ≥Grade 3 
Hold until Grade 1 or baseline, resume at 180 
mg (3 tablets)  
First occurrence of seizure of any grade or Grade 4 
neurotoxicity 
Discontinue 
More than 7 days off treatment due to treatment 
related toxicity 
Discontinue 
 
8 
Pharmaceutical Information 
8.1 Apalutamide 
Molecular Formula and Chemical Class 
Apalutamide drug substance is a white to off-white crystalline solid. 
Chemical Name: (4-[7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-
diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide) 
Chemical structure: 
                      
 
Molecular Formula: C21H15F4N5O2S 
Molecular Weight: 477.44 


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Physical Description of Study Drug(s) 
The Case 5815 tablet supplied for this study contains 60 mg of Apalutamide. It will be manufactured and 
provided under the responsibility of the sponsor. Refer to the Investigator's Brochure for a list of 
excipients. 
 
Packaging 
Apalutamide tablets (60-mg) will be packaged in 120-count, 160 cc high-density polyethylene (HDPE) 
bottles with child-resistant closures. 
 
Labeling 
Study drug labels will contain information to meet the applicable regulatory requirements. 
 
Preparation, Handling, and Storage 
The study drugs must be stored in a secure area and administered only to subjects enrolled in the 
clinical study in accordance with the conditions specified in this protocol. Refer to the pharmacy 
manual/study site investigational product manual for additional guidance on study drug preparation, 
handling, and storage. 
 
Drug Accountability 
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects must be instructed to return all original containers, whether empty 
or containing study drug. All study drug will be stored and disposed of according to the sponsor's 
instructions. Study-site personnel must not combine contents of the study drug containers. 
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form. 
 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor. 
 


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ͺǤʹ Leuprolide 
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin releasing 
hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The 
chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-
N-ethyl-L-prolinamide acetate (salt) with the following structural formula 
 
 
Leuprolide acts as an agonist at pituitary GnRH receptors. By interrupting the normal pulsatile 
stimulation of, and thus desensitizing, the GnRH receptors, it indirectly downregulates the 
secretion of gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), 
leading to hypogonadism and thus a dramatic reduction in estradiol and testosterone levels in both 
sexes. 
 
LUPRON INJECTION is a sterile, aqueous solution intended for subcutaneous injection. It is available 
in a 2.8 mL multiple-dose vial containing leuprolide acetate (5 mg/mL), sodium chloride, USP (6.3 
mg/mL) for tonicity adjustment, benzyl alcohol, NF as a preservative (9 mg/mL), and water for 
injection, USP. The pH may have been adjusted with sodium hydroxide, NF and/or acetic acid, NF. 
 
As Lupron is a standard treatment for the management of prostate cancer. All patients will receive 
this agent according to institutional guidelines. 
 
Pharmacodynamics and Pharmacokinetics 
Onset of action: Following transient increase, testosterone suppression occurs in ~2-4 weeks of 
continued therapy. 
Distribution: Males: Vd: 27 L  
Protein binding: 43% to 49%  
Metabolism: Major metabolite, pentapeptide (M-1)  
Bioavailability: SubQ: 94%  
Excretion: Urine (<5% as parent and major metabolite) 
 
 
 


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9 
Adverse Events and Potential Risks  
9.1 
Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse events regardless of 
causality and special situations excluding those from subjects not exposed to a Janssen Medicinal 
Product and product quality complaints with or without an adverse event as described in this Exhibit will 
be reported from the time a subject has signed and dated an Informed Consent Form (ICF) until 
completion of the subject’s last study-related procedure (which may include contact for follow-up 
safety).  Serious adverse events will be reported for 30 days after the last dose of study drug. 
For the purposes of this study, the Janssen medicinal product is Apalutamide.  
9.2 
Definitions  
9.2.1 
Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non- investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
 
Surgical AEs such as urinary incontinence, erectile dysfunction and wound complications will be 
assessed per institutional guidelines. These will not be captured as part of treatment related AEs. 
 
9.2.2 
Adverse Events of Special Interest 
Adverse events of special interest are events that the COMPANY is actively monitoring as a result 
of a previously identified signal (even if non-serious). 
 
There are no adverse events of special interest identified for apalutamide. 
 
 
 
 
 
 


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9.2.3 
 Identified Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements. 
• An identifiable subject (but not disclosing personal information such as the subject’s name, 
initials or address) 
• An identifiable reporter (investigational site) 
• A Janssen medicinal product 
• An adverse event, outcome, or certain special situations 
 
The minimum information required is: 
• Suspected Janssen medicinal product (doses, indication) 
• Date of therapy (start and end date, if available) 
• Batch or lot number, if available 
• Subject details (subject ID and country) 
• Gender 
• Age at AE onset 
• Reporter ID 
• Adverse event detail (AE verbatim in English), onset date, relatedness, causality, action taken, 
outcome, (if available) 
• Janssen protocol ID 
 
9.2.4 
Product Quality Complaint (PQC) 
A product quality compliant is defined as any suspicion of a product defect related to a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product, or delivery system.  Not all PQCs involve a 
subject.  Lot and batch numbers are of high significance and need to be collected whenever 
available. 
 
Examples of PQC include but not limited to: 
• Functional Problem: e.g., altered delivery rate in a controlled release product 
• Physical Defect:  e.g. abnormal odor, broken or crushed tablets/tablets 
• Suspected Contamination 
• Suspected Counterfeit 
 
9.2.5 
Serious Adverse Event (SAE) 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
 
 Results in death.  
 Is a life-threatening adverse experience.  The term life-threatening in the definition of serious 
refers to an adverse event in which the subject was at risk of death at the time of the event.  It 


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does not refer to an adverse event which hypothetically might have caused death if it were 
more severe.  
 Requires inpatient hospitalization or prolongation of existing hospitalization for AEs related 
to study drug and not for the scheduled radical prostatectomy.  Any adverse event leading to 
hospitalization or prolongation of hospitalization will be considered as Serious, UNLESS at 
least one of the following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery arranged prior 
to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
o However it should be noted that invasive treatment during any hospitalization 
may fulfill the criteria of “medically important” and as such may be reportable 
as a serious adverse event dependent on clinical judgment.  In addition where 
local regulatory authorities specifically require a more stringent definition, the 
local regulation takes precedent.  
 Results in persistent or significant disability/incapacity.  The definition of disability is a 
substantial disruption of a person’s ability to conduct normal life’s functions. 
 Is a congenital anomaly/birth defect.  
 Is a suspected transmission of any infectious agent via a medicinal product. 
 Is an important medical event.  Important medical events that may not result death, be life-
threatening, or require hospitalization may be considered a serious adverse experience when, 
based upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood disease or disorders, or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. The 
development of a new cancer is always considered an important medical event. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE EVENT WITHIN 
30-DAYS OF THE LAST DOSE OF APALUTAMIDE AS STATED IN SECTION 9.2.5.2. 
 
SAE reports and any other relevant safety information are to be emailed to Dr. Garcia at 
garciaj4@ccf.org and to the Cleveland Clinic SAE inbox at cancersaeinbox@ccf.org. 
 
SAE reports and any other relevant safety information are also to be sent to the COMPANY 
(Janssen Research & Development, LLC) within 24 hours via secure email at IIS-BIO-VIRO-
GCO@its.jnj.com as described in sections 9.7.1 and 9.9.  
 
 


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9.2.5.1 Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the hospitalization 
that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during the study 
must be reported as a serious adverse event, except hospitalizations for the following: 
• Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons such 
as pending placement in long-term care facility) 
• Surgery or procedure planned before entry into the study. [Note: Hospitalizations that were 
planned before the start of data collection and where the underlying condition for which the 
hospitalization was planned has not worsened will not be considered serious adverse events. Any 
adverse event that results in a prolongation of the originally planned hospitalization is to be 
reported as a new serious adverse event.] 
 
9.2.5.2 Life-Threatening Conditions 
The cause of death of a subject in a study within 30-days of the last dose of Apalutamide whether 
or not the event is expected or associated with the study drug, is considered a serious adverse 
event. 
 
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of efficacy 
will be reported if they fulfill the serious adverse event definition. 
 
9.3 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For a medicinal product(s) with a marketing authorization, the 
expectedness of an adverse event will be determined by whether or not it is listed in the applicable 
product information.  
 
For Apalutamide, the expectedness of an adverse event will be determined by whether or not it is listed 
in the applicable product information.  
For Apalutamide, the link to the package insert is: 
 
http://www.janssenlabels.com/package-insert/product-monograph/prescribing-
information/ERLEADA-pi.pdf 
   
 
9.4 
Special Reporting Situations  
Safety events of interest for a Janssen medicinal product that require expediting reporting and/or safety 
evaluation include, but are not limited to: 
• Drug exposure during pregnancy (maternal and paternal) 


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• Overdose of a Janssen medicinal product 
Exposure to a Janssen medicinal product from breastfeeding  
• Suspected abuse/misuse of a Janssen medicinal product 
• Inadvertent or accidental exposure to a Janssen medicinal product  
• Medication error involving a Janssen medicinal product (with or without patient exposure to the 
Janssen medicinal product, e.g., name confusion) 
• Suspected transmission of any infectious agent via administration of a medicinal product 
 
These safety events may not meet the definition of an adverse event; however, from Janssen 
Scientific Affairs perspective, they are treated in the same manner as adverse events. Special 
situations should be recorded on the Adverse Event page of the CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be recorded on a 
Serious Adverse Event Report Form and be reported to Janssen Scientific Affairs within 24 hours of 
becoming aware of the event. 
 
9.5 
Pregnancy 
Because the Janssen medicinal product may have an effect on sperm, pregnancies in partners of male 
subjects exposed to a Janssen medicinal product will be reported by the PRINCIPAL INVESTIGATOR 
within 24 hours of their knowledge of the event using the Serious Adverse Event Form.  Depending on 
local legislation this may require prior consent of the partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant 
will be required. 
 
9.6 
Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. The INSTITUTION and 
PRINCIPAL INVESTIGATOR shall provide all adverse events, both serious and non-serious, in report 
format. However, in certain circumstances more frequent provision of safety data may be necessary, 
e.g. to fulfill a regulatory request, and as such the data shall be made available within a reasonable 
timeframe at Janssen Scientific Affairs’ request. 
 
9.7 
Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Janssen  
Medicinal Products to the COMPANY 
 
All adverse events and special situations whether serious or non-serious, related or not related, 
following exposure to a Janssen medicinal product are to be documented by the investigator 
and recorded in the CRF and in the subject’s source records. Investigators must record in the 
CRF their opinion concerning the relationship of the adverse event to a Janssen medicinal 
product.  
 


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All (serious and non-serious) adverse events reported for a Janssen medicinal product should be 
followed up in accordance with clinical practice. 
 
9.7.1 SAEs and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed 
until any of the following occurs: 
 The event resolves 
 The event stabilizes 
 The event returns to baseline, if a baseline value/status is available 
 The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct 
 It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
 
 The INSTITUTION and the PRINCIPAL INVESTIGATOR will transmit all SAEs and special 
situations following exposure to a Janssen product under study in a form provided by the 
COMPANY within 24-hours of becoming aware of the event(s).  
 
 All follow-up information for serious adverse events that are not resolved at the end of 
the study or by the time of patient withdrawal must be reported directly by the PRINCIPAL 
INVESTIGATOR, within 24 hours becoming aware, to the COMPANY using the COMPANY’s 
Serious Adverse Event Report.  
 
 All available clinical information relevant to the evaluation of a related SAE, serious ADR 
or special situation is required. 
 
 The INSTITUTION and/or PRINCIPAL INVESTIGATOR are responsible for ensuring that 
these cases are complete and if not are promptly followed-up. A safety report is not 
considered complete until all clinical details needed to interpret the case are received. 
Reporting of follow-up information should follow the same timeline as initial reports. 
 
 Copies of any and all relevant correspondences with regulatory authorities and ethics 
committees regarding any and all serious adverse events, irrespective of association with 
the Janssen Product under study, are to be provided to the COMPANY within 24 hours of 
such report or correspondence being sent to applicable health authorities. 
 
9.7.2 Non-Serious AEs 
All non-serious adverse events should be reported to COMPANY according to the timeframe 


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outlined in the Research Funding Agreement section entitled Reporting of Data.   
SAE Report Form SAEs will be recorded on the FDA Form 3500A (MedWatch) but should 
only be reported as instructed below.  The electronic FDA SAE reporting forms should not be 
used.   
 
9.7.3 PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the 
protection of patients, investigators, and the COMPANY, and are mandated by regulatory 
agencies worldwide. The COMPANY has established procedures in conformity with 
regulatory requirements worldwide to ensure appropriate reporting of PQC information. Lot 
and/or Batch #s shall be collected or any reports failure of expected pharmacological action 
(i.e., lack of effect). The product should be quarantined immediately and if possible, take a 
picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported to the 
COMPANY by the PRINCIPAL INVESTIGATOR within 24 hours after being made aware of the 
event.  
 
If the defect for a Janssen medicinal product under study is combined with either a serious 
adverse event or non-serious adverse event, the PRINCIPAL INVESTIGATOR must report the PQC 
to the COMPANY according to the serious adverse event reporting timelines.  A sample of the 
suspected product should be maintained for further investigation if requested by the COMPANY. 
 
9.8 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for  
Non-Janssen Medicinal Products  
 
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen medicinal 
product under study, the PRINCIPAL INVESTIGATOR should notify the appropriate 
regulatory/competent authority or the manufacturer of that medicinal product (in the absence 
of appropriate local legislation) as soon as possible. 
 
9.9 
Transmission Methods 
The following methods are acceptable for transmission of safety information to the COMPANY: 
• 
Electronically via Janssen SECURE Email service at IIS-BIO-VIRO-GCO@its.jnj.com   
(preferred) 
• 
For business continuity purposes, if SECURE Email is non-functional: 
- 
Facsimile (fax) to 1-866-451-0371, receipt of which is evidenced in a successful fax 
transmission report 
• 
Telephone (if fax is non-functional). 
 


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Please use the contact information and process information provided by the COMPANY. 
 
9.10 Reporting Procedures for Serious Adverse Events 
 For the purposes of safety reporting, all adverse events will be reported that occur after taking the first 
dose of Apalutamide through 30 days after the final dose of study drug. Adverse events, both serious 
and non-serious, and deaths that occur during this period will be recorded in the source documents. All 
SAEs should be monitored until they are resolved or are clearly determined to be due to a subject’s 
stable or chronic condition or intercurrent illness (es). Related AEs will be followed until resolution to 
baseline or grade 1 or stabilization.  
 
 
9.11 Institutional Review Board Reporting Requirements: 
Investigative sites will report adverse events to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events.  
 
9.12 SAEs and OnCore 
 
All SAEs will be entered into OnCore.   
 
A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into OnCore 
 
9.13 Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial (internal or 
external) are reported to the Case Comprehensive Cancer Center’s Data and Safety Toxicity 
Committee. This submission is simultaneous with their submission to Janssen Scientific Affairs, 
LLC and/or other regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per CCCC Data 
and Safety Monitoring Plan. 
 
9.14 Data and Safety Monitoring Plan (DSMP) 
 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and Safety 
Monitoring Plan in accordance with NCI guidelines. 
9.15 Criteria for Defining the Severity of an Adverse Event 
9.15.1 
Severity of adverse events will be graded according to the Cancer Therapy and 
Evaluation Program (CTCAE) Common Terminology Criteria for Adverse Events v. 4.0 available at 
http://ctep.cancer.gov. For terms not specified within NCI-CTCAE, the following guideline should be 
used to determine grade: 
Table 2. Criteria for Severity of Adverse Event Terms Not Specified Within NCICTCAE 
Toxicity Grade 
Description 


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Grade 1 
Mild; asymptomatic or mild symptoms, clinical or 
diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age appropriate instrumental activities 
of daily living. 
Grade 3 
Severe or medically significant but not immediately life-
threatening; 
hospitalization 
or 
prolongation 
or 
hospitalization indicated; disabling; limiting self 
care activities of daily living 
Grade 4 
Life-threatening consequences; urgent intervention 
indicated. 
Grade 5 
Death related to AE. 
 
9.16 End of Treatment  
A patient may be discontinued from study treatment at any time if the patient, the Investigator and his 
(her) team, feels that it is not in the patient’s best interest to continue on study. The following is a list of 
possible reasons for early discontinuation of study treatment: 
 
Disease progression   
 
Any episode of seizure  
 
Any other adverse event that cannot be adequately managed with dose modifications, including 
dose interruption for up to 7 days  
 
Protocol violation requiring discontinuation of study treatment  
 
Patient is not compliant with study procedures  
 
Lost to follow-up  
 
Patient withdrawal of consent  
 
Sponsor request for early termination of study  
 
Patients will be followed for at least 28 +/-7 calendar days after the last dose of study drug. If a patient is 
withdrawn from treatment due to an adverse event, the patient will be followed until the adverse event 
has resolved or stabilized as per Section 7.6. 
9.16.1 Data to be collected for the end of treatment visit:  
 Record any adverse events (optional if performed within 1 week)  
 Record changes to concomitant medications (optional if performed within 1 week)  
 Assess study drug compliance  
 Perform abbreviated physical examination (optional if performed within 1 week)  


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 Perform and record vital signs and ECOG performance status (optional if performed within 1 
week)  
 Collect blood and urine for clinical laboratory assessments (optional if performed within 1 
week)  
 
9.16.2 
Safety Follow-Up (4-8 weeks following the Last Dose of Study Drug)   
 Record any adverse events  
 Record changes to concomitant medications  
10 Tissue Studies 
10.1 Tissue Procurement  
Radical prostatectomy tissue will be processed in a standardized fashion according to institutional 
protocols established by the Specimen Core.  Immediately after removal, prostatectomy specimens will 
be transferred into sterile ice-cold slurry of normal saline. Specimens will be accessioned and assigned a 
research number by the Tumor Procurement Service and tissue for study will be harvested according to 
standard protocols established and described in the Specimen Core and processed for pathological 
analysis as per established standards. Once harvested, the tissue to be used for this study will be snap 
frozen in liquid nitrogen and stored at -80 degrees until required for the planned analysis. All study 
related tissue (after official pathology review) will be stored within the GU core pathology department 
following standard institutional procedures and policies. Access to study tissue will be granted to 
appropriate personnel listed in the study protocol. 
 
10.2 HSD3B1 genotyping 
10.2.1 
HSD3B1 Genotyping By Sequencing 
Genomic DNA will be prepared from peripheral blood using DNeasy Blood and Tissue Kit (QIAGEN, 
Germantown, MD). HSD3B1 genotyping will be determined through a melting curve analysis on an 
ABI 7500 Real Time PCR System (Applied Biosystem, Carlsbad, CA). To determine genotype of 
HSD3B1, primer set ( Forward: 5’-GTCAAATAGCGTATTCACCTTCTCTTAT-3’ and Reverse 5’- 
GAGGGTGGAGCTTGATGACATCT-3’) and  probe (GGAGA+ACCTGAAGTCCAAGACTCAGTGATTAAGG) 
will be used. The assay will consist of an initial denaturing set at 95̊C for 2m, followed by 
amplification for 60 cycles of 95̊C for 30s, 66̊C for 30s and 75̊C for 30s. A melting curve will follow 
amplification (95̊C for 30s, 25̊C for 60s, 50̊C for 15s and final ramp rate (0.3%-1%) to 95̊C for 15s. 
Each reaction will be done with 40 ng DNA, 50nM forward primer, 500nM reverse primer, and Light 
scanner HRM LC green Master Mix (Biofire Diagnostics, Salt Lake City, Utah). 
 
10.2.2 
HSD3B1 Genotyping by Melting Curve Assay 
Genomic DNA will be prepared from peripheral blood using DNeasy Blood and Tissue Kit (QIAGEN, 
Germantown, MD). PCR products of the promoter region, all exons, exon-intron junctions and the 


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30-UTR will be sequenced to identify mutations in HSD3B1. To sequence the 30 flanking region of 
HSD3B1, primer set (Forward: 50-ATGTGGAGGGAGGTGTGAGT-30 and Reverse: 50-
ACGGAGATGGGTCTCTTCCA-30 ) will be used with an annealing temperature of 62_C. Genotyping 
PCR reaction (50 ml) will be done with 30-100 ng genomic DNA, 1 x PCR buffer with 0.2 mM dNTP, 
0.2 mM of each primer, and 0.5 ml Phusion High-Fidelity DNA Polymerase (New England BioLabs 
Inc, Ipswich, MA).  1 mL purple top tube will be used for genotyping purposes at indicated time 
points.  
10.3 Immunohistochemical Staining Of Cellular And Molecular Markers In Prostate Tumor Tissue 
IHC for PSA will be performed as routinely done by Dr. Cristina Magi-Galluzzi in the pathology 
department at the Cleveland Clinic. 
10.4 Steroid Extraction and Measurements 
Prostate tissue (20mg) will be homogenized using a Minilyse bead homogenizer (Bergin Corp, Rockville, 
MD). Steroids and internal standard will be extracted using methyl tart Butyl-ether (Sigma-Aldrich, St. 
Louis, MO). Steroids will be derivative using a Girard T reagent (Sigma-Aldrich, St. Louis, MO) as 
previously described (22). Steroid concentrations will be assessed through stable isotope ratios and 
quantitated using developed methodology on a liquid chromatography mass spectrometer.  1 10mL red 
top tube will be used for serum steroid studies at indicated time points.   
10.5 mRNA Expression  
Prostate tissue (<20 mg) will be homogenized and RNA will be extracted using a Gene lute 
Mammalian Total RNA Miniprep Kit ( Sigma Aldrich, St. Louis, MO). Extracted RNA will be 
synthesized into cDNA using an iScript cDNA Synthesis Kit (Bio-Rad, Hercules, CA). Expression for 
PSA, TMPRSS2, FKBP5, EZH2, H3K27, and UBE2C will be assessed by quantitative real time PCR on 
an ABI 7500 Real Time PCR System (Applied Biosystem, Carlsbad, CA). Each reaction (20µL) will 
consist of 100-500 ng of synthesized cDNA, 500 nM each forward and reverse primer set, and 10 
µL of iTaq Universal SYBR Green Supermix ( Bio-Rad, Hercules, CA). The qPCR protocol consists of 
an initial denaturation at 95̊C for 2m followed by 40 cycles of 95̊C for 3s and 60̊C for 35s, with a 
final hold at 4̊C. AR-Responsive gene expression will be normalized to housekeeping gene RPLPO. 
The rationale behind these exploratory analyses derives from existing data demonstrating that 
alterations of the androgen-regulated TMPRSS2 and ETS transcription factor genes in prostate 
cancer tissue leads to worse outcome. Similarly, FKBP5, EZH2, H3K27, and UBE2C are considered 
potential prognostic putative cancer stem cell markers that have been associated with tumor 
aggressiveness and might be altered by the use of Apalutamide and leuprolide therapy 


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11 Study Calendar  
Table 2. Study Calendar 
 
Eligibility 
screening 
Cycle 1,  Day 
(-28)g 
Pre-op 
evaluation 
(1 to 3 days 
before 
surgery) 
Prostatectomy 
(Day of 
surgery)K 
off 
Apalutamide 
follow-up visit in 
4 -8 weeks  after 
RPh 
Leuprolide IM injection + 
Apalutamide distribution  
 
Xa 
 
 
Tissue Core Biopsy from Initial 
Diagnosis 
 
X 
 
 
MRI Prostate b 
 
 
 
 
Informed consent 
 
X 
 
 
Demographics 
 
X 
 
 
Medical History 
 
X 
X 
X 
Prior and concomitant 
medication review c 
 
X 
X 
X 
Vital Signs 
 
X 
X 
X 
Height/Weight/BSA 
 
X 
X 
X 
Physical Exam 
 
X 
X 
X 
Performance Status 
 
X 
X 
X 
CBC/diff, platelets 
 
X 
XJ 
X 
Serum chemistriesd 
 
X 
XJ 
X 
TSHL 
 
X 
X 
X 
PT/PTT 
 
X 
XJ 
 
Genotyping Analysis 
Xe 
 
 
 
 
Evaluation of AE's 
 
X 
X 
 
X 
PSA 
 
X 
XI 
 
 
Testosterone, DHEA, DHEA-S, 
Androstenedione, Direct Renin 
and Aldosterone/Direct Renin 
Ratio 
 
X 
XI 
 
 
Blood for Correlative Studiesf 
X 
 
 
X 
 
a: Study agents include Apalutamide. Patients will receive these medications for the entire 
treatment course at Day (-28) ± 3 days up to and including the day before prostatectomy (day of 
surgery).    
b: MRI of the prostate will be completed at the discretion of the treating Physician. Although this 
imaging technique is routinely done at the Cleveland clinic prior to patients undergoing RP, it will 
desired but not be mandatory for study entry. 
c: Refer to Section 7.3 for further details on reporting prior and concomitant medications. 
d: Sodium, potassium, chloride, CO2, BUN, Creatinine, Glucose, LFT’s (AST/ALT/Alkaline  
Phosphatase, Albumin, LDH, total bilirubin), and Calcium. Testosterone, PSA, DHEA, DHEA-S and 


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AD levels will be measured within 28 days of treatment initiation and at the end of C1 of therapy 
as above. 
e: Blood will be drawn for HSD3B1 genotyping for the research laboratory.  
f: Blood draw for steroid concentration in the serum and to understand how tumors use and make 
hormones. This sample will be sent to Dr Sharifi’s lab. 
g: Laboratory tests and procedures must be completed on Cycle 1 Day (-28) or within 28 days prior 
to the start of study agents Leuprolide IM injection and Apalutamide distribution.  
h: Post-operative follow up visit will ideally occur between 4 and 8 weeks after surgery. Time line 
may vary in order to coordinate with Urology follow up visit.  
I: Allowable window for lab collection is 1-3 days prior to, or on, the day of prostatectomy.  
J: Allowable window for lab collection is 1-7 days prior to prostatectomy.  
K: Must be completed within 28 days ±3 from the start of Leuprolide IM injection and 
Apalutamide distribution.  
L: Thyroid stimulating hormone (TSH) should be evaluated throughout the study (with T3 and T4 
done only if TSH is abnormal) as follows: On Cycle 1 or within 28 days before treatment initiation, 
at the end of Cycle 1 (approximately day 28 Pre-op evaluation), and 4-8 weeks after RP (Follow Up 
evaluation). 


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12 Measurement of Effect 
12.1 Benign and malignant tissue concentration of DHT and other androgen (testosterone (T), 
dehydroepiandrosterone (DHEA), androstenediol, 5α-androstanedione (5α-dione), 
androstenedione (AD), androsterone and 5α-androstanediol), Direct renin and Aldosterone/Direct 
Renin Ratio will be measured by IHC as stated in section 10 of the protocol. 
12.2 PSA, FKBP5, TMPRSS2, EZH2, H3K27, and UBE2C expression in benign and malignant prostate 
tissue after neoadjuvant leuprolide and Apalutamide will be also analyzed by IHC and qPCR as 
noted in section 10 of the protocol. 
12.3 Toxicity will be evaluated using standard CTC guidelines as per section 9 of the protocol. All 
patients enrolled on study will be evaluable for toxicity from the time of their first treatment with 
leuprolide and Apalutamide. Surgical safety data will be captured following standardized surgical 
templates routinely used in the GU clinic.  
12.4 Although clinical endpoints are not the aim of this biologic study, results of the surgical pathology 
and PSA changes pre-treatment, during treatment and after surgery will be collected. 
13 
Records to Be Kept/ Regulatory Considerations 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 9. Adverse 
Events: List and Reporting Requirements). 
13.1 
Data Reporting  
2.3 
The Forte EDC™ and OnCore™ databases will be utilized, as required by the Case Comprehensive 
Cancer Center and Cleveland Clinic, to provide data collection for both accrual entry and trial data 
management. Forte EDC and OnCore™ are Clinical Trials Management Systems housed on secure 
servers. Access to data through Forte EDC and OnCore™ is restricted by user accounts and 
assigned roles. Once logged into the Forte EDC or OnCore™ system with a user ID and password, 
Forte EDC™ and OnCore™ define roles for each user which limits access to appropriate data. User 
information and password can be obtained by contacting the OnCore™ Administrator at OnCore-
registration@case.edu for OnCore™ access, and taussigoncore@ccf.org for Forte EDC™ access. 
2.4 
 


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Forte EDC™ is designed with the capability for study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification.  When properly utilized, Forte EDC™ is 21 CFR 11 
compliant.  This study will utilize electronic Case Report Form completion in the Forte EDC™ database. A 
calendar of events and required forms are available in Forte EDC™. 
 
13.2 
Regulatory Considerations  
The study will be conducted in compliance with ICH guidelines and with all applicable federal (including 
21 CFR parts 56 & 50), state or local laws.  
13.2.1 Written informed consent 
Provision of written informed consent must be obtained prior to any study-related 
procedures.  The Principal Investigator will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risks and benefits of the 
study as well as the subject’s financial responsibility.  Subjects must also be notified that 
they are free to discontinue from the study at any time.  The subject should be given the 
opportunity to ask questions and allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed 
written Informed Consent Form must be given to the subject. 
13.2.2 Subject data protection  
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to subject’s 
medical information that includes all hospital records relevant to the study, including 
subjects’ medical history. 
 
13.2.3 Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, case report forms, source documents, 
records of study drug receipt and dispensation, and all IRB correspondence for as long as 
needed to comply with national and international regulations and the institution in which 
the study will be conducted, or for the period specified by the sponsor, whichever is longer. 
No records will be destroyed until the Principal Investigator confirms destruction is 
permitted.  
 


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13.2.4 Audits and inspections 
Authorized representatives of the Cleveland Clinic’s clinical trials office, a regulatory 
authority, an Independent Ethics Committee (IEC), a designee from the Cleveland Clinic’s 
Institutional Review Board (IRB), or a Janssen Scientific Affairs, LLC representative may 
visit the Center to perform audits or inspections, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, Good Clinical Practice (GCP), guidelines of the International Conference on 
Harmonization (ICH), and any applicable regulatory requirements.   
13.2.5    Data safety and monitoring plans 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI regulations.  
13.2.6    Patient’s financial responsibilities during the study 
13.2.6.1  There will be no cost for the Apalutamide  or any of the correlative histologic 
and/or molecular studies. Leuprolide is considered standard of care in men with prostate 
cancer thus it will be billed to patient’s insurance. 
13.2.6.2 Charges incurred to pre-surgical evaluation, such as monitoring complete blood 
counts, comprehensive metabolic panel, and other necessary tests per surgical protocols 
will be charged to the patient's insurance company in standard fashion. 
13.2.6.3 Charges incurred to monitor the safety and efficacy of this treatment, such as 
monitoring complete blood counts, comprehensive metabolic panel, baseline 
testosterone level and PSA, which are not indicated per patient’s standard treatment 
plan, will be paid by the study grant. 
 


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14 Biostatistical Considerations 
All subjects will be receiving Apalutamide starting day (-28) ± 3 days from the scheduled RP date and will 
be genotyped for HSD3B1 before enrollment in the study as a part of the screening. We expect a higher 
concentration of DHT in patients with homozygous HSD3B1(1245C) genotype as a result of flux to DHT 
due to 3βHSD1 abundance.  
14.1  Sample Size and Accrual 
In a recent report by Chang et al24 the prevalence of the homozygous HSD3B1(1245C) genotype was 10% 
in 40 CRPC patients. The prevalence however is to some extent race-dependent.25  
The prevalence of the wild type and heterozygous genotypes were approximately 2:1, and therefore the 
homozygous variant genotype is “rate-limiting” for accrual. The target enrollment is 12 patients who 
have the homozygous HSD3B1(1245C) genotype, 15 patients who are heterozygous, and 30 wild-type 
patients. Because of the low prevalence of homozygous  HSD3B1 (1245C), enrollment in each cohort will 
proceed until its target is reached. A subject who e i t h e r prematurely discontinues from the 
study before completing 28 days of the treatment,  prior to surgery, or for whom we are 
unable to obtain a tissue sample from,  may be replaced in order to achieve target enrollment in 
each cohort.  All safety and efficacy data from all accrued patients independent of the availability of 
post-treatment tumor material will be collected and analyzed. 
Overall, based on the prevalence of the homozygous variant genotype, we predict that we may need to 
screen up to 120 patients to reach our accrual objective. Due to logistical restrictions, an accrual goal of 
80 male patients may be needed in order to capture all objectives for a sample size of 57 patients. 
Accrual is expected to be approximately 2 years in the three cohorts.  
With 57 patients there will be statistical power >80% to detect a 4-fold trend in the primary endpoint, 
DHT concentrations in the resected prostate tissue, as well as similar trends in other androgens and 
molecular markers. The calculation is based on a 2-sided test with 5% type I error; a codominance model 
where there is a 4-fold difference in hormone concentration between the wild-type and homozygous 
variant genotypes and a concentration approximately mid-way between the two for the heterozygous 
genotype; and that variability in this concentration could be as much as 125% of the mean hormone 
tissue concentration for each genotype. Note that 125% of the mean is a conservative estimate of 
variability. If it turns out in fact to be lower – e.g. similar to the 75% seen in a recent study in which 
patients were treated with 6 months leuprolide prior to RP35 , there will be >95% power to detect a 4-
fold range, >90% to detect a 3-fold range, and 75% to detect a 2-fold range.   
14.2   Data Analysis  
Hormone concentrations and tissue PSA, TMPRSS2, FKBP5, EZH2, H3K27, and UBE2C measured by qPCR 
will be summarized as means and standard errors, possibly after data transformation. Differences 
between genotypes within and between tissue types will be analyzed using linear or non-linear models. 


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Pearson or Spearman rank correlations will be used to assess associations between the concentrations 
of the different hormones and molecular markers. All tests of statistical significance will be two-sided. 
 
 


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15 References 
1. SEER Stat Fact Sheets: Prostate Cancer. at <http://seer.cancer.gov/statfacts/html/prost.html> 
2. OH, W. K. & Kantoff, P. Management of Hormone Refractory Prostate Cancer: Current Standard and 
Future Prospects. J. Urol. 160, 1220–1229 (1998). 
3. Chi, K. N. et al. Castration-resistant Prostate Cancer: From New Pathophysiology to New Treatment 
Targets. Eur. Urol. 56, 594–605 (2009). 
4. Taplin, M.-E. & Balk, S. P. Androgen receptor: A key molecule in the progression of prostate cancer to 
hormone independence. J. Cell. Biochem. 91, 483–190 (2004). 
5. Sedelaar, J. P. M. & Isaacs, J. T. Tissue culture media supplemented with 10% fetal calf serum contains 
a castrate level of testosterone. The Prostate 69, 1724–1729 (2009). 
6. Montgomery, R. B. et al. Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A 
Mechanism for Castration-Resistant Tumor Growth. Cancer Res. 68, 4447–4454 (2008). 
7. Sharifi, N., Dahut, W. L. & Figg, W. D. Secondary hormonal therapy for prostate cancer: what lies on 
the horizon? BJU Int. 101, 271–274 (2008). 
8. Attard, G. et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the 
treatment of castration-resistant prostate cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 27, 3742–
3748 (2009). 
9. Ryan, C. J. et al. Phase I Clinical Trial of the CYP17 Inhibitor Abiraterone Acetate Demonstrating 
Clinical Activity in Patients With Castration-Resistant Prostate Cancer Who Received Prior 
Ketoconazole Therapy. J. Clin. Oncol. 28, 1481–1488 (2010). 
10. 
Navarro, D., Luzardo, O. P., Fernández, L., Chesa, N. & Dı́az-Chico, B. N. Transition to androgen-
independence in prostate cancer. J. Steroid Biochem. Mol. Biol. 81, 191–201 (2002). 
11. 
Mostaghel, E. A. et al. Resistance to CYP17A1 inhibition with abiraterone in castration resistant 
prostate cancer: Induction of steroidogenesis and androgen receptor splice variants. Clin. Cancer Res. 
Off. J. Am. Assoc. Cancer Res. 17, 5913–5925 (2011). 
12. 
Feldman, B. J. & Feldman, D. The development of androgen-independent prostate cancer. Nat. 
Rev. Cancer 1, 34–45 (2001). 
13. 
Grossmann, M. E., Huang, H. & Tindall, D. J. Androgen Receptor Signaling in Androgen-
Refractory Prostate Cancer. J. Natl. Cancer Inst. 93, 1687–1697 (2001). 
14. 
Scher, H. I., Buchanan, G., Gerald, W., Butler, L. M. & Tilley, W. D. Targeting the androgen 
receptor: improving outcomes for castration-resistant prostate cancer. Endocr. Relat. Cancer 11, 459–
476 (2004). 
15. 
Rathkopf, D. E. et al. Phase I Study of Apalutamide, a Novel Antiandrogen, in the Treatment of 
Castration-Resistant Prostate Cancer. J. Clin. Oncol. 31, 3525–3530 (2013). 
16. 
Lorence, M. C., Murry, B. A., Trant, J. M. & Mason, J. I. Human 3 beta-hydroxysteroid 
dehydrogenase/delta 5----4isomerase from placenta: expression in nonsteroidogenic cells of a 
protein that catalyzes the dehydrogenation/isomerization of C21 and C19 steroids. Endocrinology 
126, 2493–2498 (1990). 
17. 
Simard, J. et al. Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 
isomerase gene family. Endocr. Rev. 26, 525–582 (2005). 


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18. 
Cai, C., Wang, H., Xu, Y., Chen, S. & Balk, S. P. Reactivation of Androgen Receptor Regulated 
TMPRSS2:ERG Gene Expression in Castration Resistant Prostate Cancer. Cancer Res. 69, 6027–6032 
(2009). 
19. 
Evaul, K., Li, R., Papari-Zareei, M., Auchus, R. J. & Sharifi, N. 3beta-hydroxysteroid 
dehydrogenase is a possible pharmacological target in the treatment of castration-resistant prostate 
cancer. Endocrinology 151, 3514–3520 (2010). 
20. 
Scher, H. I. & Sawyers, C. L. Biology of Progressive, Castration-Resistant Prostate Cancer: 
Directed Therapies Targeting the Androgen-Receptor Signaling Axis. J. Clin. Oncol. 23, 8253–8261 
(2005). 
21. 
Ryan, C. J. & Tindall, D. J. Androgen Receptor Rediscovered: The New Biology and Targeting the 
Androgen Receptor Therapeutically. J. Clin. Oncol. 29, 3651–3658 (2011). 
22. 
Chang, K.-H. et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-
resistant prostate cancer. Proc. Natl. Acad. Sci. U. S. A. 108, 13728–13733 (2011). 
23. 
Shah, S. K. et al. Phase II Study of Dutasteride for Recurrent Prostate Cancer During Androgen 
Deprivation Therapy. J. Urol. 181, 621–626 (2009). 
24. 
Chang, K.-H. et al. A Gain-of-Function Mutation in DHT Synthesis in Castration-Resistant Prostate 
Cancer. Cell 154, 1074–1084 (2013). 
25. 
http://genome.ucsc.edu/. 
26. 
Hearn, J. W. D. et al. HSD3B1 and resistance to androgen deprivation therapy in prostate cancer. 
J. Clin. Oncol. 33, (2015). 
27. 
Efstathiou, E. et al. Cytoreduction and androgen signaling modulation by abiraterone acetate 
(AA) plus leuprolide acetate (LHRHa) versus LHRHa in localized high-risk prostate cancer (PCa): 
Preliminary results of a randomized preoperative study. J. Clin. Oncol. 30, (2012). 
28. 
Taplin, M.-E. et al. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate 
(LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate 
cancer (LHRPC): Results of a randomized phase II study. J. Clin. Oncol. 30, (2012). 
29. 
Medivation, Inc. Study of MDV3100 as a Neoadjuvant Therapy for Patients Undergoing 
Prostatectomy for Localized Prostate Cancer [ClinicalTrials.gov identifier NCT01547299] US National 
Institutes of Health; (2012). at <https://clinicaltrials.gov/ct2/show/study/NCT01547299> 
30. 
Attard, G. et al. Phase I Clinical Trial of a Selective Inhibitor of CYP17, Abiraterone Acetate, 
Confirms That Castration-Resistant Prostate Cancer Commonly Remains Hormone Driven. J. Clin. 
Oncol. 26, 4563–4571 (2008). 
31. 
Ercole, C. E. et al. Dehydroepiandrosterone metabolism in fresh human prostate: A feasibility 
study. J. Clin. Oncol. 32, (2014). 
32. 
Tamae, D. et al. Development, validation and application of a stable isotope dilution liquid 
chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-
LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum. J. Steroid Biochem. 
Mol. Biol. 138, 281–289 (2013). 
33. 
Foster, W. R. et al. Drug safety is a barrier to the discovery and development of new androgen 
receptor antagonists. The Prostate 71, 480–488 (2011). 


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34. 
Rathkopf, D. et al. Phase I dose-escalation study of the novel antiandrogen BMS-641988 in 
patients with castration-resistant prostate cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 17, 
880–887 (2011). 
35. 
Taplin, M.-E. et al. Intense Androgen-Deprivation Therapy With Abiraterone Acetate Plus 
Leuprolide Acetate in Patients With Localized High-Risk Prostate Cancer: Results of a Randomized 
Phase II Neoadjuvant Study. J. Clin. Oncol. 32, 3705–3715 (2014). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 APPENDIX I  
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light 
housework, office work). 
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. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely 
disabled, 
hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
  
 
 


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APPENDIX II 
Subject Registration Form 
Protocol CASE5815 
Title: The Association between HSD3B1 Genotype and Steroid 
Metabolism in Normal and Prostate Cancer Tissue of Men with 
Intermediate and High-risk Prostate Cancer Undergoing Radical 
Prostatectomy after Treatment with Apalutamide and 
Leuprolide.   
Date: 
___/___/_____ 
Subject Demographics 
Study Site: Cleveland Clinic  
MRN: 
 
Last Name: 
First Name 
MI: 
Gender: 
 
X    Male 
 
Ethnicity: 
 
□    Hispanic 
□    Non-Hispanic 
□    Unknown 
 
  
Race: 
□   American Indian or Alaska Native 
□   Asian 
□   Black or African American 
□   Native Hawaiian or Other Pacific Islander 
□   Unknown 
□   White 
Date of Birth: 
___/___/_____ 
On Study Date: 
___/___/_____ 
Study Patient  No: 
 
Disease Site:     PROSTATE 
Histology:    PROSTATE 
Registrar’s Name  
Registrar’s Signature 
 
 
 


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APPENDIX III 
 
 
IRB CASE 5815 Study Medication Diary 
 
Subject Initials_________ Subject Number____________ Cycle ________ 
 
Take 4 tablets at the same time once a day with or without food. 
Take at approximately the same time each day. 
Last does of Apalutamide will be taken the day before surgery. 
Please record the time and number of tablets you take each day on the table below: 
Cycle 
Day 
 
Date 
Time of 
Daily Dose 
Number 
of 
Tabs 
taken 
 
Side Effects 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
Signature of patient:  
 
Signature__________________________________________ Date ________________ 


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APPENDIX IV 
Medications Prohibited while on active treatment with Apalutamide 
 
Generic Name 
Brand Name* 
aminophylline 
Aminocont; Aminomal; Diaphyllin; Filotempo; Neophyllin; Norphyl; 
Phyllocontin; Syntophyllin; Tefamin; Truphylline; Xing You Shan;  
aminophylline in 
combination 
Asmeton; Cha Xin Na Min; Emergent-Ez; Fufang Dan An Pian; Ke Zhi 
 
amitriptyline 
Amirol; Amitrip; Amixide; Deprelio; Diapatol; Elatrol; cElatrolet; Elavil; 
Endep; Enovil; Emitrip; Klotriptyl; Laroxyl; Levate; Limbitrol; Limbitryl; 
Mutabase; Mutabon; Nobritol; Novo-Triptyn; Pertriptyl; Redomex; 
Saroten; Sarotex; Sedans; Syneudon; Teperin; Triptizol; Triptyl; Tryptizol 
amitriptyline in 
combination 
PMS-Levazine 
 
bupropion 
 
Aplenzin; Buproban; Contrave; Elontril; Forfivo; Fortivo XL; Le Fu Ting; 
Prexaton; Quomem; Voxra; Wellbutrin; Wellbutrin XL; Wellbutrin SR; Yue 
Ting; Zyban 
chlorpromazine 
Aminazin; Chlorazin; Hibernal; Klorproman; Largactil; Megaphen; 
Ormazine; Plegomazin; Solidon; Taroctyl;Thorazine; Vegetamin; 
Wintermin; Zuledin 
Note: in Ireland also called “Clonazine” – very easy to confuse with 
clozapine. 
clozapine 
Azaleptin; Clopine; Closastene; Clozaril; CloZAPine; Denzapine; Elcrit; 
Fazacio ODT; Klozapol; Lanolept; Leponex; Lozapine; Nemea; Ozapim; 
Synthon, Versacloz; Zaponex 
desipramine  
Deprexan; Norpramin; Nortimil; Pertofrane 
doxepin 
Adapin; Anten; Aponal; Deptran; Gilex; Li Ke Ning; Quitaxon; Silenor; 
Sinepin; Sinequan; Zonalon 
imipramine 
Impril; Melipramin; Mipralin; Norfranil,; Novo-Pramine; Persamine; 
Pertofram; Pryleugan; Talendep; Tofranil; Tolerade 
lithium 
Arthriselect; Camcolit; Carbolith; Carbolithium; Eskolith; Hypnorex; Li-
Liquid; Licarbium; Limas; Liskonum; Litarex; Lithane; Lithicarb; Lithioderm; 
Lithionit; Lithobid; Liticarb; Litiomal; Lito; Maniprex; Neurolepsin; Plenur; 
Priadel; Quilonorm; Quilonum; Saniquiet; Sedalit; Teralithe 
lithium in combination 
Boripharm No 23; Emser Salz; Girheulit HOM; Helidonium-Plus; Heweurat 
N; rheuma-loges; Rhus Toxicodendron Compose; Rhus-Plus; Ricinus 
Compose 
maprotiline 
Cronmolin; Deprilept; Ludiomil; Mapromil; Melodil; Neuomil; Psymion 


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meperidine/pethidine 
Alodan ; Atropine and Demerol; Centralgine ; Demerol ; Dolantin ; 
Dolantina,; Dolantine ; Dolargan,; Dolcontral,; Dolestine ; Dolosal ; Dolsin; 
Fada; Hospira; Liba; Mepergan ; Meprozine,; Mialgin,; Opystan; Pethidine ; 
Petigan Miro ; Psyquil compositum 
meperidine/pethidine  
in combination 
Pamergan P100 
 
mesoridazine 
Serentil, Mesorin 
mirtazapine 
 
Arintapin; Avanza; Axit; Combar; Esprital; Mi Er Ning; Miro; Mirta TAD; 
Mirtabene; Mirtachem; Mirtadepi; Mirtagamma; Mirtalan; MirtaLich; 
Mirtamylan; Mirtaron; Mirtaz; Mirtazelon; Mirtazon; Mirtazonal; Mirtel; 
Mirtin; Mirtor; Mirzaten; Norset; Noxibel; Paidisheng; Psidep; Remergil; 
Remergon; Remeron; Remirta; Rexer; Yarocen; Zispin 
olanzapine 
Anzorin, Arenbil; Arkolamyl; Atyzyo; Bloonis; Clingozan; Egolanza; Lansyn; 
Lanzek; Lazapix; Nolian; Nykob; Olafid; Olanzaran; Olanzep; Olanzin; 
Olanzine; Olapin; Olasyn; Olazax; Olpinat; Olzapin; Olzin; Ou Lan Ning; 
Ozilormar; Parnassan; Ranofren; Sanza; Stygapon; Synza; Ximin; Zalasta; 
Zamil; Zappa; Zapris; Zerpi; Zolafren; Zolaxa; Zonapir; Zopridoxin; Zylap; 
Zypadhera; Zypine; Zyprexa; Zyprexa Relprew; Zydis 
olanzapine in 
combination 
Symbyax 
 
risperidone 
Aleptan; Apo-Risperid; Arketin; Calmapride; Diaforin; Doresol; Hunperdal; 
Jing Ping; Ke Tong; Leptinorm; Lergitec; Orizon; Ozidal; Perdox; 
Ranperidon; Resdone; Ridal; Ridonex; Rileptid; Ripedon; Risepro; Rispa; 
Rispaksole; Rispefar; Rispemylan; Rispen; Rispera; Risperanne; Risperdal; 
Risperdalconsta; Risperdaloro; Risperigamma; Risperon; Rispolept; 
Rispolux; Rispond; Rispons; Risset; Rixadone; Rorendo; Ryspolit; Si Li Shu; 
Sizodon; Speridan; Suo Le; Torendo; Zhuo Fei; Zhuo Fu; Ziperid; Zoridal 
theophylline 
Aerolate; Afonilum; Aminomal; An Fei Lin; Apnecut; Apo-Theo; Asmalix; 
Asmalon; Bi Chuan; Bronchoparat; Bronchoretard; Cylmin; Diffumal; 
Elixifilin; Elixophyllin; Etipramid; Euphyllin; Euphyllina; Euphylline; 
Euphylong; Frivent; Gan Fei Lin; Nuelin; Protheo; Pulmophylline; Quelesu; 
ratio-Theo-Bronc; Respicur; Retafyllin; Shi Er Ping; Slo-Bid; Slo-Phyllin; 
Telbans; Teotard; Terdan; Teromol; Theo-24; Theo-Dur; Theo; Theochron; 
Theodur; Theofol; Theolair; Theoplus; Theospirex; Theostat ;  Theotard; 
Theotrim; Theovent; Tromphyllin; Unicon; Unicontin; Unifyl; Uniphyl; 
Uniphyllin Continus; Uniphyllin; UniXan; Xanthium; Xi Fu Li; Yan Er 
theophylline in 
combination 
Antong; Baladex; Bi Chuan; Binfolipase; Broncho-Euphyllin; Broncomar; 
Do-Do ChestEze; Elixophyllin-GG; Elixophyllin-KI; Insanovin; Marax ; 
Neoasma; Theofol Comp; Theophedrinum-N; Xu Hong; Yi Xi Qing 
thioridazine 
Detril; Elperil; Melleril; Ridazin; Ridazine; Thiodazine; Thioril; Sonapa 
ziprasidone 
Geodon; Li Fu Jun An; Pramaxima; Si Bei Ge; Ypsila; Zeldox; Zipwell; 
Zypsila; Zypsilan 


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herbal products 
All herbal products must be discontinued if applicable, per provider 
discretion  
 
steroid therapy 
Systemic steroid therapy (inhaled or topical steroids); Corticosteroids; 
unless waived at the provider’s discretion.  
 
** Note:  this document is intended as an aid in identifying prohibited meds, but due to the global 
scope of the Apalutamide studies may not be all inclusive.  
 
 
 

ICF_001.pdf: 
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