Prospective Study of Apalutamide and Abiraterone Acetate iN ChemoTHerapy-Naïve mEn With mCRPC Stratified by Race
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Daniel George, MD

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Prospective study of Apalutamide and Abiraterone Acetate iN ChemoTHerapy-
Naïve mEn with mCRPC Stratified by Race (PANTHER)  
Sponsor-Investigator: 
Daniel George, MD – Duke Cancer Institute 
Funding Source: 
Janssen Scientific Affairs, LLC 
Study Drug Source: 
Protocol Source: 
Janssen Scientific Affairs, LLC 
Daniel George, MD - Duke Cancer Institute 
Duke IRB#: 
Pro00075097 
IND# 
134175 
Principal Investigator 
Daniel George, MD 
Sub-Investigators 
Andrew Armstrong, MD 
Michael Harrison, MD 
Statistician 
Susan Halabi, PhD 
Correlative Science Investigators 
Andrew Nixon, PhD  (Duke University) 
Jennifer Freedman, PhD  (Duke University) 
Nima Sharifi, MD (Cleveland Clinic) 
Rick Kittles, PhD (City of Hope) 
Elahe Mostaghel, MD, PhD (Fred Hutch Cancer Center 
and University of Washington) 
Robert Montgomery, MD (Fred Hutch Cancer Center  
and University of Washington) 
Massimo Loda, MD (Weill Cornell Medicine) 
Sara Bleve, MD (Weill Cornell Medicine) 
David Nanus, MD (Weill Cornell Medicine) 
ver 01   January 9, 2017 
ver 02   March 1, 2017 
ver 03   March 12, 2017 
ver 04  April 19, 2017 
ver 05  July 25, 2017 
ver 05a  Nov 13, 2017 
ver 06  Mar 22, 2018 
 
ver 07  July 19, 2018 
ver 08 April 12, 2019  
ver 09 August 03, 2020 
ver 10 January 10, 2022 
ver 11 May 3, 2024 
ver 12 October 04, 2024 
NCT03098836

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Responsible Study Personnel 
Principal Investigator 
Daniel George, MD 
 
  
 
Regulatory Coordinator 
 
Steven Gray,  PhD, RAC 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
Duke Cancer Network (DCN) Participating Sites 
Clinical Sites 
Research Affiliates 
Site PI : Dr. Daniel George, MD 
  
Lumberton:  Southeastern Regional Medical 
Center / Gibson Cancer Center 
Laurinburg:  Scotland Health Care System 
 
Smithfield:   Johnston Memorial Hospital 
Authority: 
Johnston Cancer Center, Smithfield, NC  
Johnston Hem/Onc of Clayton, NC 
 
 
 
Virginia Oncology Associates 
Site Lead Inv: Dr Mark Fleming, MD 
 
 
Spartanburg Regional 
Gibbs Cancer Center & Research Institute 
Site Lead Inv:  Michael Humeniuk, MD 
 
 
 
 
 
External Sites Participating in This Study 
Barbara Ann Karmanos Cancer Institute 
Site PI: Elizabeth Heath, MD 
 
 
Tulane University 
Site PI: Brian Lewis, MD 
 
 
University of North Carolina at Chapel Hill 
Site PI: Young Whang, MD 
  
 

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Chesapeake Urology 
Site PI: Ronald Tutrone 
 

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Table of Contents 
LIST OF ABBREVIATIONS ................................................................................................................. 7 
1. 
SYNOPSIS ................................................................................................................................. 8 
2. 
SCHEDULE OF EVENTS ........................................................................................................... 15 
3. 
CURRENT TREATMENT FOR METASTATIC CRPC ................................................................... 18 
4. 
Rationale for Current Study .................................................................................................. 19 
4.1 
ABIRATERONE ACETATE  ............................................................................................................ 19 
4.2 
APALUTAMIDE ........................................................................................................................... 21 
4.3 
Rationale .................................................................................................................................... 22 
5. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................... 25 
5.1 
Study objectives ......................................................................................................................... 25 
5.2 
Study endpoints ......................................................................................................................... 26 
6. 
INVESTIGATIONAL PLAN ....................................................................................................... 27 
6.1 
Overall study design .................................................................................................................. 27 
6.2 
Study population ........................................................................................................................ 28 
6.3 
Inclusion and exclusion criteria .................................................................................................. 28 
7. 
PATIENT REGISTRATION ........................................................................................................ 31 
7.1 
Informed Consent ...................................................................................................................... 31 
7.2 
Lead Site Registration ................................................................................................................ 32 
7.3 
Institutional Registration ........................................................................................................... 32 
8. 
TREATMENTS ........................................................................................................................ 33 
8.1 
Abiraterone acetate ................................................................................................................... 33 
8.2 
Apalutamide .............................................................................................................................. 35 
8.3 
Concomitant therapy ................................................................................................................. 36 
8.4 
Treatment compliance ............................................................................................................... 38 
9. 
STUDY ASSESSMENTS ........................................................................................................... 39 
9.1 
Vital signs, performance status, and physical exam ................................................................. 39 
9.2 
Laboratory evaluations .............................................................................................................. 39 
  
 
  
 

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9.3 
ECG............................................................................................................................................. 40 
9.4 
Imaging ...................................................................................................................................... 40 
9.5 
Exploratory correlative studies .................................................................................................. 40 
9.6 
End of treatment........................................................................................................................ 44 
9.7 
Follow up safety visit ................................................................................................................. 44 
9.8 
Follow-Up for Radiographic Progression ................................................................................... 44 
9.9 
Follow-Up for Overall Survival ................................................................................................... 45 
10. 
MONITORING AND MANAGEMENT OF SUSPECTED ABIRATERONE ACETATE AND 
APALUTAMIDE TOXICITY ............................................................................................................... 45 
10.1 
Management of Drug-Related Adverse Events ......................................................................... 45 
10.2 
Interruption or discontinuation of treatment ............................................................................ 50 
11. 
SAFETY ASSESSMENTS AND REPORTING .......................................................................... 51 
11.1 
Definitions .................................................................................................................................. 51 
11.2 
Unlisted (Unexpected) Adverse Event/Reference Safety Information ....................................... 53 
11.3 
Special Reporting Situations ...................................................................................................... 54 
11.4 
Maintenance of Safety Information .......................................................................................... 55 
11.5 
Procedures for Reporting to JANSSEN SCIENTIFIC AFFAIRS ....................................................... 55 
11.6 
Management of Adverse Events, Serious Adverse Events and Special Reporting Situations .... 57 
11.7 
Recording of Adverse Events, Serious Adverse Events and Special Reporting Situations .......... 58 
11.8 
Reporting Timelines ................................................................................................................... 58 
11.9 
FDA Reporting Requirements .................................................................................................... 59 
11.10 
Dissemination of Safety Information from JANSSEN SCIENTIFIC AFFAIRS to 
INSTITUTION/PRINCIPAL INVESTIGATORS .............................................................................................. 59 
12. 
EFFICACY ASSESSMENTS ................................................................................................... 60 
12.1 
Baseline tumor evaluation ......................................................................................................... 60 
12.2 
Response Criteria ....................................................................................................................... 61 
12.3 
Confirming time-to-event outcomes .......................................................................................... 64 
12.4 
Duration of overall response ..................................................................................................... 64 
12.5 
Radiographic Progression-free survival ..................................................................................... 64 
12.6 
Secondary endpoint assessments .............................................................................................. 65 
12.7 
Exploratory endpoints ................................................................................................................ 66 
13. 
STATISTICAL METHODS ..................................................................................................... 67 

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14. 
DATA REPORTING AND REGULATORY REQUIREMENTS ................................................... 68 
14.1 
Data Entry .................................................................................................................................. 68 
14.2 
Study monitoring and quality assurance ................................................................................... 69 
14.3 
Data Safety and Monitoring ...................................................................................................... 70 
15. 
PROTOCOL AMENDMENTS OR CHANGES IN STUDY CONDUCT ....................................... 71 
16. 
PROCEDURES AND INSTRUCTIONS ................................................................................... 71 
16.1 
Disclosure and confidentiality.................................................................................................... 71 
16.2 
Discontinuation of study ............................................................................................................ 72 
16.3 
Ethics and Good Clinical Practice ............................................................................................... 72 
REFERENCES .................................................................................................................................. 74 
APPENDIX 1:  PERFORMANCE STATUS CRITERIA .......................................................................... 77 
APPENDIX 2:  CYP450 ISOENZYME INHIBITORS AND INDUCERS TO BE USED WITH CAUTION .... 78 
APPENDIX 3:  NCI COMMON TOXICITY CRITERIA ......................................................................... 82 
APPENDIX 4:  CRITERIA FOR DISEASE PROGRESSION ................................................................... 83 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
AKT  
See PKB (protein Kinase B) 
ALT  
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
AST  
Aspartate aminotransferase 
BUN  
Blood Urea Nitrogen 
CBC  
Complete Blood Count 
cfDNA Cell-free DNA 
CK  
Creatine Kinase 
CR  
Complete Response 
CRF 
Case report forms 
CRPC 
Castration resistant prostate cancer 
CT  
Computed Tomography 
CTCAE  Common Terminology Criteria for Adverse 
Events 
ECG  
Electrocardiogram 
ECHO  Echocardiogram 
FFPE 
Formalin-fixed, paraffin-embedded  
GCP  
Good Clinical Practice 
GWAS Genome Wide Association Study  
HIV  
Human Immunodeficiency Virus 
ICH  
International Conference on Harmonization 
IEC  
Independent Ethics Committee 
IRB  
Institutional Review Board 
mCRPC Metastatic castration-resistant prostate 
cancer 
MRI  
Magnetic Resonance Imaging 
PC 
Prostate cancer 
PD  
Progressive Disease 
PET  
Positron Emission Tomography 
PFS 
Progression free survival 
PIN 
Prostatic intraepithelial neoplasia 
PK  
Pharmacokinetic 
PKB  
Protein Kinase B (or AKT) 
PR 
Partial response 
PT  
Prothrombin Time 
PTT  
Partial Thromboplastin Time 
QTc 
QT interval (corrected) 
RBC  
Red Blood Cells 
REB  
Research Ethics Board 
RECIST  Response Evaluation in Solid Tumors 
SAE  
Serious adverse event 
SD 
Stable disease 
SNP       Single Nucleotide Polymorphism 
TTP  
Time to Progression 
ULN  
Upper Limit of Normal 
WBC  
White Blood Count 

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[9-12].  Thus, germline polymorphisms of these differentially expressed genes also may have important implications with 
regard to response to therapy targeted towards the androgen signaling pathway.    In addition, our laboratory has 
identified a number of novel alternatively spliced genes in African American versus Caucasian prostate cancer and have 
shown that African American variants track with more aggressive cancer invasion characteristics of prostate cancer in 
African American men (Bi-Dar Wang, Jennifer A. Freedman, Daniel J. George, Norman H. Lee and Steven R. Patierno, 
manuscript in preparation).  Moreover, we have identified novel single nucleotide polymorphisms located in splicing 
regulatory regions of such genes that associate with prostate cancer risk, aggressiveness and survival (Jennifer A. 
Freedman, Yanru Wang, Hongliang Liu, Patricia G. Moorman, Terry Hyslop, Daniel J. George, Norman H. Lee, Qingyi Wei 
and Steven R. Patierno, manuscript in preparation).  Subsets of these genes are androgen receptor targets.  Therefore, 
germline polymorphisms of these alternatively spliced genes also may have important implications with regard to 
response to therapy towards the androgen signaling pathway.  
To what extent racial differences affect response and time to progression on secondary hormonal therapies in the CRPC 
setting are unknown.  A retrospective analysis of the COU-AA-302 study included only 28 black patients but demonstrated 
trends in favor of median rPFS and 90% decline from baseline PSA in this subpopulation vs the entire population [79]. 
Similarly, a retrospective case-controlled analysis of patients treated at Duke University with abiraterone prednisone pre 
or post docetaxel chemotherapy revealed statistically significant improved PSA response rate in African American vs 
Caucasian patients by 30% decline (77.8% vs 54.4%; p=0.008) and 50% decline (68.9% vs 48.9%; p=0.028) with trends in 
favor of 90% PSA decline (37.8%, vs. 28.9%)  [80]. In addition, primary abiraterone-refractory disease (PSA increase as best 
response) trended to be more in Caucasian than in African American patients (31.1% vs 15.6%; p=0.052).   Based upon 
these findings we hypothesized that African American CRPC patients may be more sensitive to abiraterone prednisone 
than Caucasian patients.  We have conducted a prospective Phase II study of abiraterone acetate and prednisone in 
patients with mCRPC, stratified by self-described race in order to test this hypothesis (Abi Race Clinicaltrials.gov 
NCT01940276).  Secondarily, to what extent differences in systemic hormonal levels as well as androgen transport gene 
polymorphisms affect response to abiraterone acetate is unknown. Understanding any potential differences in response 
to therapy by race and/or by hormonal/genetic factors could impact on both our clinical use of abiraterone acetate as well 
as future clinical trial design. Finally, as other agents targeting the androgen/androgen receptor pathways become 
available, it will be important to differentiate their activity according to race, genetics and hormonal milieu.   
Apalutamide is a competitive AR inhibitor that is fully antagonistic to AR overexpression, lacking significant agonist 
activity, , or inducing activity for AR nuclear localization or DNA binding [81]. In Phase I testing apalutamide was dosed 
between 30 mg and 480 mg once daily, resulting at all dose levels and a median 50% decline from baseline PSA at 12 
weeks of 47% [82].  The most frequently reported adverse event was grade 1/2 fatigue (47%). A phase II multicenter 
study evaluated the clinical efficacy of apalutamide at 240 mg daily in non-metastatic (nm) CRPC patients.  In 51 evaluable 
patients 89% had ≥50% PSA decline at 12 weeks. Median time to PSA progression was 24.0 mo (95% confidence interval 
[CI], 16.3 months - not reached [NR]); median metastasis-free survival was NR (95% CI, 33.4 months - NR). The most 
common AE was fatigue (any grade, n=31 [61%]) [83]. A Phase III Study of apalutamide versus placebo in men with 
nmCRPC showed that apalutamide prolonged metastasis-free survival and time to symptomatic progression. [89] 
Abiraterone acetate and apalutamide are not FDA approved in combination. The concept of combining apalutamide with 
abiraterone prednisone derives from their potentially complimentary mechanisms of action in which apalutamide 
functions as a pure androgen receptor antagonist while abiraterone inhibits cholesterol metabolism into androgen, thus 
lowering the functional levels of ligand for the receptor.  Since most patients who progress on abiraterone do so with a 
rising PSA we believe the androgen receptor remains a driver of disease progression in patients treated with abiraterone 
prednisone alone.  Together, apalutamide and abiraterone may be able to more completely inhibit the androgen – 
androgen receptor axis and provide greater clinical benefit.  An ongoing Phase III study (ACIS) is evaluating whether the 
combination of apalutamide, abiraterone acetate and prednisone improves radiographic progression-free survival 
compared to abiraterone acetate, prednisone and placebo (clinicaltrials.gov NCT02257736). Like the COU-AA-302 study, 
the ACIS trial is international and not likely to contain a significant proportion of African American patients, leaving 

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unanswered the question of whether African American patients may have a genetic propensity for response and clinical 
benefit to this combination.   
We propose a Phase II Multisite, prospective study to evaluate radiographic PFS in men with mCRPC stratified by self-
described race and treated with apalutamide, abiraterone acetate and prednisone. Secondary endpoints will describe the 
response to apalutamide, abiraterone acetate and prednisone, PSA kinetics, as well as safety and tolerability. Exploratory 
endpoints will describe the incidence and associations of key hormone and lipid  levels,  germline polymorphisms in 
androgen signaling genes and genes that have been shown to be differentially expressed and/or alternatively spliced  in 
African American versus Caucasian prostate cancer, cell-free plasma DNA profiles, pharmacokinetics of abiraterone 
acetate and plasma-based biomarkers in both African American and Caucasian cohorts.  
Primary Objective:  The primary goal is to estimate the radiographic PFS distribution separately in African American and 
Caucasian men with mCRPC treated with apalutamide, abiraterone acetate and prednisone. 
Secondary Objectives:  
1) PSA kinetics: to determine  the duration of PSA response, time to nadir, and percent of men who achieve a PSA < 0.1  
2) Radiographic assessments: to estimate the rate of objective response and incidence of bone flares 
3) Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension in the two populations 
4) Overall survival 
Exploratory Objectives: 
1. Perform ancestral genotyping to obtain genetically estimated indicators of race using DNA isolated from whole blood 
at baseline. 
2. Describe the baseline profile of serum hormone levels (including but not limited to testosterone, DHT, DHEA, DHEAS, 
estradiol) and lipids, the change in levels with subsequent therapy (Cycle 4), and their correlation with response to 
abiraterone acetate plus apalutamide.   
3. Abiraterone Pharmacokinetics (PKs) drawn at cycle 1 d1 at 1, 2, 4, 8 hours post dose and cycle 2 d1 at  (24 hour 
trough), 1, 2, 4, 8 hours post dose 
4. Describe the germline SNP profiles of the androgen receptor gene, target genes involved in androgen metabolism 
and signaling and target genes that have been shown to be differentially expressed in African American and in 
Caucasian prostate cancer and their associations with response to abiraterone acetate, prednisone plus apalutamide. 
The status of the aforementioned targets will also be assessed in archival tumor tissue, if available. 
5. Describe the expression and splicing profiles of the androgen receptor gene, target genes involved in androgen 
metabolism and signaling and target genes that have been shown to be differentially expressed and/or spliced in 
African American and in Caucasian prostate cancer and their associations with response to abiraterone acetate, 
prednisone plus apalutamide. The status of the aforementioned targets will also be assessed in archival tumor tissue, 
if available. 
6. Describe cell-free plasma DNA profiles and their associations with response to abiraterone acetate, prednisone plus 
apalutamide. 
7. To explore the associations between baseline levels and treatment-related changes of plasma-based protein markers 
with response in patients treated with abiraterone acetate, prednisone plus apalutamide. 
8. Describe abiraterone metabolism by race with particular attention to active metabolites including D4A and 3-keto-
5α-abiraterone. 
9. To assess the concordance between the genomic alterations identified in cfDNA to the genomic alterations identified 
in the tumor-derived DNA 
 
 
 
 
 
 
 

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Permitted Concomitant Treatment:  
(see full list of permitted concomitant treatments in Section 8.3.1) 
• 
Standard therapies for preexisting conditions, medical/surgical complications including nausea and diarrhea, 
and palliation. 
• 
Non-potent P450 CYPs isoenzyme inhibitors and/or inducers (Appendix 3). 
• 
LHRH agonists or antagonists. 
• 
Anti-hypertensive medications. 
• 
Diabetic medications. 
• 
Antidepressants or other medications for mood disorders.   
• 
Analgesics including opioids are allowed provided KPS remains 70 or greater. 
• 
Bisphosphonates and/or denosumab. 
• 
Erythropoietic agents. 
• 
Systemic anticoagulation with Coumadin and low molecular weight heparin. 
• 
Focal therapies for localized non-prostate cancers 
• 
Provenge, after the first 3 cycles on treatment are completed 
Study Intervention and Administration:  The study agent abiraterone acetate will be administered at a dose of 1000 mg 
orally once daily and apalutamide 240 mg orally once daily with prednisone 5 mg BID in 4-week cycles throughout the 
treatment period.   Abiraterone acetate must be taken on an empty stomach. No food should be consumed for at least 
two hours before the dose of abiraterone acetate is taken and for at least one hour after the dose of abiraterone acetate 
is taken. Abiraterone acetate should be taken with a glass of water and consumed over as short a time as possible.  
Patients should swallow the tablets whole and not chew them.   There are no specific requirements with respect to 
dosing and food for taking the apalutamide. The subject must have the ability to swallow, retain, and absorb oral 
medication. Apalutamide and abiraterone acetate will be provided by Janssen Scientific Affairs, LLC and distributed by DCI 
Investigational Chemotherapy Service.  The study drug provided must be dispensed in the original packaging.  Patients 
will be instructed to take a 5-mg prednisone tablet, twice daily.  Prednisone will be obtained commercially. It is not 
required for the prednisone to be taken at the same time as abiraterone acetate or apalutamide. The dose of prednisone 
will remain unchanged in the event that the study drug dose is changed. If a prednisone dose is missed, it should be 
omitted and will not be made up.  Should a dose modification of the prednisone be needed due to toxicities, the site will 
need to discuss this with the Sponsor-Investigator. 
Study Assessments:   
Vital signs, performance status, and physical exam will be assessed at each visit.   The following laboratory studies will be 
obtained at intervals specified in the study flow chart to assess subject safety, specifically the risk of infection, 
hyperglycemia, and/or bone marrow, liver, thyroid and kidney abnormalities:  complete blood count, TSH, blood urea 
nitrogen (BUN), creatinine, sodium, potassium, calcium,  glucose, albumin, total protein, total bilirubin, alkaline 
phosphatase, AST (SGOT), ALT (SGPT) LDH.   
 
For efficacy assessment, a PSA will be drawn at screening and prior to each scheduled study visit per the schedule of 
events. A CT scan with contrast of chest, abdomen, and pelvis, and a bone scan will be performed within 42 days prior to 
cycle 1 day 1 visit and every 3 cycles (12 weeks).  
 
Correlative Science:  
Whole blood will be collected in purple top EDTA tubes at baseline for DNA isolation.  Isolated DNA will be used for ancestral 
genotyping to obtain genetically estimated indicators of race and for characterization of SNPs of androgen metabolism and 
signaling genes as well as genes that have been shown to be differentially expressed in African American versus Caucasian 
prostate cancers. A genome wide association study (GWAS) is planned in both African American and Caucasian men with 
mCRPC and their association with response to abiraterone acetate plus apalutamide, in line with the specified endpoints 
and biomarkers defined in the trial. In addition, blood will be collected in PAXgene Blood RNA Tubes at baseline, Cycle 4, 
and at progression or end of treatment for RNA isolation and characterization of differential expression and/or splicing of 

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the androgen receptor gene, TMPRSS2-ERG gene fusion, androgen metabolism and signaling genes and genes that have 
been shown to be differentially expressed and/or spliced in African American versus Caucasian prostate cancer. Blood will 
also be collected at baseline, Cycle 2, and at progression or end of treatment in EDTA tubes for cell-free plasma DNA isolation 
and characterization. Moreover, baseline assessments of lipidomics and hormonal levels, including but not limited to 
testosterone, DHT, DHEA, DHEAS and estradiol and their change after 12 weeks on therapy will be evaluated from collected 
serum. Furthermore, abiraterone pharmacokinetics (PKs) will be drawn on C1D1 at 1, 2, 4 and 8 hours post dose of study 
drug and C2D1 at 24 hour trough, 1, 2, 4 and 8 hours post dose of study drug.  Finally blood will be collected at baseline, 
cycle 2 and at progression or end of treatment in EDTA tubes and plasma samples will be isolated to explore additional 
biomarkers that may have prognostic or predictive value. In addition to blood, paraffin-embedded archival tumor tissue will 
be collected whenever available from all patients having undergone a diagnostic core biopsy or a surgery (prostatectomy or 
metastatic sampling).  
Safety Evaluation:   
Subjects receiving at least one dose of apalutamide and/or abiraterone acetate will be evaluable for safety.   
• 
Safety will be assessed by physical exam, laboratory assessments, review of concomitant medications, 
adverse event (AE) and serious adverse event (SAE) evaluations every cycle throughout the study. 
• 
Electrocardiogram prior to initiation and subsequently at the discretion of the treating physician   
• 
NCI Common Toxicity Criteria (v 4.0) will be used to record and monitor for adverse events (Appendix 3). 
Treatment will be held and/or dose reduced for certain specified grade 3 or 4 adverse events until resolution to 
grade 1 as specified in the protocol 
Efficacy Evaluation:   
The primary endpoint will be radiographic progression free survival (rPFS) based on modified PCWG3 criteria or based on 
the onset of a skeletal related event.  Imaging will be obtained every 12 weeks. 
Secondary endpoints will include: 
1. PSA kinetics: to determine  the duration of PSA response, time to nadir, and percent of men who achieve a PSA < 
0.1;  
2. Radiographic assessments: to estimate the rate of objective response and incidence of bone flares 
3. Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension in the two populations 
 
Statistical Considerations:  
Sample Size justification  Based on Ryan et al. the median time to radiographic progression free survival (rPFS) for 
Abiraterone acetate in mCRPC patients is 16.5  months [14]. This trial is non-comparative. Fifty (50) patients will be 
enrolled in each group (AA and Caucasians). With an accrual rate of 50 patients/group over 20-month accrual period, 24-
months follow-up, and assuming that rPFS follows an exponential distribution, based on 5000 simulations the average 
width of a two-sided 95% confidence interval for the median rPFS is 16.  
Data Analysis Point estimates (median rPFS and proportion) and 95% confidence limits for the rPFS and the proportion of 
patients who experience PSA decline of 30%, 50% and 90% will be calculated. In addition, post therapy changes in PSA will 
be explored as a continuous outcome. The Kaplan-Meier product limit method will be used to estimate the PSA PFS and 
rPFS.  
The GWAS analysis will be mostly exploratory as the trial limited sample size will not permit definitive analyses.  Call rate, 
patterns of missing data, and departures from the Hardy-Weinberg equilibrium will be performed using exact test to 
identify SNPs that will not be used in analysis.   Allele frequencies will be estimated within each racial group separately. 
Although race is self reported, admixture estimates and will be adjusted for in the analysis. Test for association will be 
performed under an additive model. 
Ethical Considerations:  
This study will be conducted in accordance with applicable laws and regulations including, but not limited to, the ICH GCP 
and the ethical principles that have their origins in the Declaration of Helsinki.  The IRB must review and approve the 
protocol and ICF before any subjects are enrolled.  Before any procedures specified in the protocol are performed, the 
subject must sign and date the IRB-approved ICF. 
 

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1. 
Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics, 2012. CA Cancer J Clin, 2012. 
62(1): p. 10-29. 
2. 
Litman, H.J., et al., Serum androgen levels in black, Hispanic, and white men. J Clin 
Endocrinol Metab, 2006. 91(11): p. 4326-34. 
3. 
Mohler, J.L., et al., Racial differences in prostate androgen levels in men with clinically 
localized prostate cancer. J Urol, 2004. 171(6 Pt 1): p. 2277-80. 
4. 
Carson, A.P., et al., Trends and racial differences in the use of androgen deprivation therapy 
for metastatic prostate cancer. J Pain Symptom Manage, 2010. 39(5): p. 872-81. 
5. 
Holmes, L., Jr., et al., Impact of androgen deprivation therapy on racial/ethnic disparities in 
the survival of older men treated for locoregional prostate cancer. Cancer Control, 2009. 
16(2): p. 176-85. 
6. 
Giovannucci, E., et al., The CAG repeat within the androgen receptor gene and its 
relationship to prostate cancer. Proc Natl Acad Sci U S A, 1997. 94(7): p. 3320-3. 
7. 
Ross, R.W., et al., Inherited variation in the androgen pathway is associated with the 
efficacy of androgen-deprivation therapy in men with prostate cancer. J Clin Oncol, 2008. 
26(6): p. 842-7. 
8. 
Yang, M., et al., SLCO2B1 and SLCO1B3 may determine time to progression for patients 
receiving androgen deprivation therapy for prostate cancer. J Clin Oncol, 2011. 29(18): p. 
2565-73. 
9. 
Powell, I.J., et al., Genes associated with prostate cancer are differentially expressed in 
African American and European American men. Cancer Epidemiol Biomarkers Prev, 2013. 
10. 
Reichardt, J.K., et al., Genetic variability of the human SRD5A2 gene: implications for 
prostate cancer risk. Cancer Res, 1995. 55(18): p. 3973-5. 
11. 
Wallace, T.A., et al., Tumor immunobiological differences in prostate cancer between 
African-American and European-American men. Cancer Res, 2008. 68(3): p. 927-36. 
12. 
Wang, B.D., et al., Androgen receptor-target genes in african american prostate cancer 
disparities. Prostate Cancer, 2013. 2013: p. 763569. 
13. 
Scher, H.I., et al., Design and end points of clinical trials for patients with progressive 
prostate cancer and castrate levels of testosterone: recommendations of the Prostate 
Cancer Clinical Trials Working Group. J Clin Oncol, 2008. 26(7): p. 1148-59. 
14. 
Ryan, C.J., et al., Abiraterone in Metastatic Prostate Cancer without Previous 
Chemotherapy. New England Journal of Medicine, 2013. 368(2): p. 138-148. 
 

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Footnotes to Schedule of Events: 
a. 
Screening/ evaluations must be completed within 30 days prior to Cycle 1 Day 1 (C1D1) dosing, with the exception of informed consent and scans (42 days).  
b. 
If the CBC with differential, Serum Chemistries, and PSA are performed within 7 days of Cycle 1 Day 1 visit, do not repeat these at the Cycle 1 Day 1 visit unless requested by 
the site’s PI. 
c. 
The end of treatment visit is to occur no more than 7 days after the last dose of study agent or within 7 days of the decision to stop drug.      
d. 
The follow-up safety visit is to occur 28 days (+/- 7 days) after the last dose of study agent. This may be combined with the end of treatment visit if the window allows.  CT 
and bone scan will be done at the safety follow up visit if scans have not been done within the last 8 weeks of the visit.  Subjects who discontinue treatment due to reasons 
other than radiographic progressive disease will be followed every 3 months (+/- 14 days) until a new treatment is started or disease progression (for up to 24 months from 
the start of study therapy).  Disease progression will be obtained through Standard of Care scans. All subjects will be followed for survival every 6 months +/- 1 month (by 
phone or chart review).   
e. 
Medical history, physical examination and AE assessments will be performed prior to dispensing each supply of study drug to patient.    An end-of-study medical history, 
physical exam, and AE assessment will be performed at the end of treatment or at progression.  In addition, one safety follow-up visit with medical history, physical exam, 
and AE assessment will occur 30 +/- 7 days of the last dose of study drug 
f. 
Vital signs (BP, pulse, respirations, temperature and weight) will be recorded at each visit.  Height will be measured at screening only.   Patients will check their blood 
pressures at least monthly (independent at home) and more often if elevated, as directed by the study team. An elevated blood pressure is >140/90. Blood pressure CTCAE 
grading will be done based on the blood pressure reading, not the number of blood pressure medications the subject is taking.   
g. 
Karnofsky performance status (Appendix 1) will be evaluated and recorded at all clinic visits on study.   
h. 
Electrocardiogram prior to initiation and subsequently at the discretion of the treating physician.   
i. 
As part of routine tumor assessment, CT and bone scans will be performed within 42 days prior to C1D1visit and every 3 cycles (approximately every 12 weeks) thereafter 
(i.e., Screening,  Day 1 of cycles 4, 7, 10 and every 3 cycles).  The timing of the scans will be within 7 days of the next planned cycle initiation.  A CT scan will be performed at 
the above described time points with contrast as per radiology protocol of chest, abdomen, and pelvis. If the chest CT at screening is clear, chest x-rays may be used for 
subsequent assessments at the enrolling physician’s discretion.  These tumor assessments will be performed locally, in strict accordance with the RECIST 1.1 guidelines.  A 
total body bone scan will be performed at the above described time points and interpreted according to modified PCWG3 guidelines (Appendix 4).  CT and bone scan 
modalities per standard institutional practices may be used, but the same modality should be used throughout the study for each subject.  Note: during screening, 
metastatic disease may be confirmed by prostate cancer-specific imaging without meeting RECIST 1.1 criteria. 
j. 
Abiraterone acetate and apalutamide will be dispensed directly from clinic. Both study drugs should be kept in the original packaging at all times. For C1D1 and C2D1, 
abiraterone acetate will be taken in the presence of the coordinator. This will allow the coordinator to document the exact time of dosing (abiraterone acetate) and to time 
the PKs accurately. Subject may take prednisone and apalutamide with food 2 hours before abiraterone acetate dose. Abiraterone acetate is taken without food. 
Alternatively, prednisone and apalutamide may be taken 1 hour after abiraterone acetate dose, with food.   
k. 
Standard-of-care laboratory assessments at the times indicated include:   
Complete blood count (CBC) with differential: WBC count with differential, platelet count, hemoglobin, and hematocrit at screening, Cycle 1 Day 15, Day 1 of  cycles 1, 2, 
3, 4 etc. every 3 cycle visits scheduled per protocol, at the end of treatment visit and at safety follow-up visit. 
Serum chemistries:  Sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, glucose, carbon dioxide or bicarbonate, calcium,  total protein, albumin, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT),  total bilirubin, and alkaline phosphatase at screening,  Cycle 1 Day 15, Day 1 of cycles 1, 2, 3, 4 etc. 
every 3 cycle visits scheduled per protocol, at the end of treatment visit, and at the end of Safety Follow-up Visit. 
LDH can be drawn at screening (or C1D1 prior to first dose) then day 1 of each cycle that has a visit scheduled per protocol and end of treatment. 
TSH at screening, every day 1 of cycles 2, 3, 4, then every 3 cycles and end of treatment. If TSH is abnormal obtain a T3/T4.  
PSA:  Drawn at screening, Day 1 of Cycle 1 and cycles 1, 2, 3, 4, etc. and every cycle that has a visit scheduled per protocol, and at the end of treatment visit. 
Testosterone:  Drawn at screening and at C4D1. 
Note: Cycle 1 Day 1 CBC, Serum Chemistries, & PSA lab tests do not have to be repeated if screening lab tests are obtained within 7 days prior to Cycle 1 Day 1 visit.   
l. 
Serum hormone levels including but not limited to testosterone (ultrasensitive) DHT, DHEA, DHEAS, and estradiol: One 5ml gold top tube will be collected at screening (or 
C1D1 prior to first dose), at Cycle 4 Day 1, and at the end of treatment visit (end of treatment research labs may be drawn at safety follow up visit if needed). Serum 

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lipidomics will also be assessed at screening (or C1D1 prior to first dose). C4D1 and end of treatment (EOT).  Lipidomic samples should be collected after fasting. See lab 
manual for detailed instructions. 
m. Plasma for blood-based biomarkers and cfDNA: Two 10ml lavender top tubes will be collected at screening (or C1D1 prior to first dose), C2D1, and end of treatment (end of 
treatment research labs may be drawn at safety follow up visit if needed.  Cell-free DNA (cfDNA) will be analyzed at screening (or C1D1 prior to first dose) and end of 
treatment.  
n. 
Whole blood DNA isolation ancestral genotyping and characterization of SNPs: One 4ml lavender top tube will be collected at screening (or C1D1 prior to first dose), See lab 
manual for detailed instructions. 
o. 
PAXgene blood RNA isolation and characterization: One 2.5 ml PAXgene Blood RNA tube will be collected at screening (or C1D1 prior to first dose), C4D1, and at end of 
treatment (end of treatment research labs may be drawn at safety follow up visit if needed. See lab manual for detailed instructions. 
p. 
PKs drawn at C1D1 at 1, 2, 4, 8 hours post dose and cycle 2 D1 at 0 (24 hour trough), 1, 2, 4, 8 hours post dose. Document timing of abiraterone acetate doses for C1D1, 
C1D28, and C2D1 on the Duke Research PK Sample Flowsheet. There is a +/-15 minute window for all PKs that are drawn except for the 8 hour time point. The 8 hour time 
point has a +/-1 hour window.  
q. 
If available and consistent with local regulations, banked tumor tissue  will be obtained (in accordance with the lab manual) and evaluated to assess somatic expression 
and/or splicing and mutation of the androgen receptor gene, target genes involved in androgen metabolism and signaling and/or target genes that have been shown to be 
differentially expressed and/or spliced in African American versus Caucasian  prostate cancer potentially predictive of abiraterone acetate  plus apalutamide antitumor 
activity. See lab manual for detailed instructions. 
r. 
C4D1 only (do not collect on C7D1, C10D1, etc.). 
s. 
May be collected on C1D1 prior to first dose. 

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3. 
CURRENT TREATMENT FOR METASTATIC CRPC 
Metastatic Castrate Resistant Prostate Cancer 
Globally, 307,000 men die of prostate cancer each year (87).  In the United States, with an 
estimated 180,890 new cases of prostate cancer and 26,120 deaths (88). Prostate cancer has 
the second highest death rate of any cancer, almost all of which occurs as a result of the 
development of metastatic castration-resistant prostate cancer. Optimizing treatments for the 
management of advanced prostate cancer is urgently needed. 
 
Prostate cancer is hormone sensitive at the time of initial diagnosis. Although most patients 
with advanced metastatic disease initially respond to conventional androgen deprivation with 
medical or surgical castration, the median duration of disease control has been 13-22 months 
and historically overall survival may be as short as 28-36 months from starting androgen 
deprivation therapy [1-3]. The clinical status of patients after failure of castration is commonly 
referred to as castration-resistant prostate cancer (CRPC). Patients with metastatic CRPC have a 
very limited life expectancy of 1-5 years and most often die of their prostate cancer. 
 
In the castrate state, remaining ligands to the AR have been thought to be derived primarily 
from the adrenal glands. Conventional androgen deprivation therapy removes 90% of 
circulating androgens produced in the gonads. As much as 10% of circulating testosterone 
remains, in part due to the peripheral conversion of adrenal steroids to testosterone. In 
addition, several recent studies suggest that androgen levels in the microenvironment of 
prostate cancer may be maintained in spite of reduced systemic levels [4, 5].  In patients with 
castrate levels of testosterone, the tissue levels of dehydroepiandrosterone, 
dihydrotestosterone, and androstenedione all remain sufficient to activate the AR. 
Furthermore, the ARs are predominately located in the nucleus in biopsy tissue, indicating 
ligand-binding and the activation of androgen-dependent gene expression. Increased 
expression of the AR is common in advanced prostate cancer, and allows lower ligand levels to 
more strongly activate the AR [6]. A recent investigation made the observation that in high risk 
primary prostate tumors and in metastatic biopsies, CYP17A1 gene expression is highly 
upregulated, suggesting the possibility of in situ production of androgens as autocrine or 
paracrine growth factors despite castration.[7, 8] Similarly, investigators at MD Anderson 
Cancer Center also detected CYP17 expression by immunohistochemistry in bone marrow 
metastasis in CRPC [9]. Although these preliminary findings require further corroborating 
evidence, the need to suppress androgen production in adrenal glands and possibly at tissue 
levels persists in CRPC. 
 
Complete androgen independence in CRPC is thought to be rare. A few patients (9%) have 
mutations in the AR; these changes could allow the AR to be activated by non-androgen ligands, 
or might allow ligand-independent AR association with coactivator molecules.[10] 

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Although gene fusions are well known to drive the development of blood cancers and 
sarcomas, only rarely have they been detected in the common solid cancers. Recent evidence 
indicates that a gene fusion may be important in the pathogenesis of prostate carcinoma.[11-
15] Chromosomal translocations involving the androgen-responsive gene transmembrane 
protease serine 2 (TMPRSS2) and erythroblast transformation–specific (ETS)-related 
transcription factors ETV1, ETV4, and ETV5, have been identified in 50% to 70% of prostate 
cancer cases.[11, 12] Translocation of TMPRSS2 to the ERG gene, found in a high proportion of 
human prostate cancer, results in overexpression of the 3'-ERG sequences joined to the 5'-
TMPRSS2 promoter. ERG and other ETS family members are transcription factors that are 
implicated in the control of cell growth and differentiation and the chimeric protein product of 
the gene translocation appears to retain hormone responsiveness.[13] Specific translocations in 
primary tumors have been associated with more aggressive natural clinical history, more 
advanced disease at diagnosis and greater lethality.[14-17] These gene rearrangements may be 
associated with tumor response to androgen deprivation therapy, including abiraterone acetate 
[18]. 
 
4. 
RATIONALE FOR CURRENT STUDY 
4.1 
ABIRATERONE ACETATE   
Abiraterone Acetate and Mechanism of Action 
Abiraterone acetate is [17-(3-pyridyl)androsta-5,16-dien-3β-ol] and is a steroidal inhibitor of 
CYP17 (17α hydroxylase/C17,20-lyase) that blocks two important enzymatic activities in the 
synthesis of testosterone (Figure 1), based on the observation that nonsteroidal 3 pyridyl esters 
improve selectivity for inhibition of 17α-hydroxylase/C17,20 lyase. Abiraterone acetate is a 
potent inhibitor with an apparent inhibition constant of 0.5 nM. Pharmacodynamic studies 
demonstrated that its effects on adrenal steroid synthesis were consistent with its mechanism 
of action. Antitumor effects were evident with PSA response and durable objective responses 
using Response evaluation criteria in solid tumors (RECIST) criteria in Phase 1 and Phase 2 
studies conducted to date.[19] Abiraterone acetate in combination with prednisone is FDA 
approved for the treatment of patients with metastatic castration-resistant prostate cancer and 
metastatic high-risk castration-sensitive prostate cancer. 
 
Abiraterone acetate is the 3-acetylated analog of abiraterone and thus a pro-drug of 
abiraterone. The chemical nomenclature of abiraterone acetate is 3β acetoxy-17-(3- pyridyl) 
androsta-5, 16-diene; its empirical formula is C26H33NO2 and molecular weight is 391.55. Once 
absorbed after oral administration, abiraterone acetate is rapidly converted to the active form, 
abiraterone (Figure 2). In initial research studies, abiraterone acetate was the predominant, if 
not the only, metabolite of abiraterone acetate detected in blood, both in preclinical studies 
and in previously conducted clinical studies.[20, 21]   

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More recently, metabolitic analyses of abiraterone in mice and in humans reveal that 
abiraterone is converted to Δ (4)-abiraterone (D4A), which inhibits additional enzymes, involved 
in androgen synthesis (CYP17A1, 3βHSD and SRD5A) and directly antagonizes the androgen 
receptor [84].  Furthermore, D4A is converted to at least three 5α-reduced and three 5β-
reduced metabolites in human serum [85]. The initial 5α-reduced metabolite, 3-keto-5α-
abiraterone, is present at higher concentrations than D4A in patients with prostate cancer 
taking abiraterone, and is an androgen receptor agonist, which may promote prostate cancer 
progression [85]. 
Figure 1. The Enzyme Complexes Inhibited by Abiraterone acetate 
 
Figure 2. Prodrug Abiraterone Acetate is Converted to Abiraterone after Absorption 
 
 
Clinical Trials with Abiraterone Acetate and Prednisone  
 

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COU-AA- 301 was a randomized, double-blind, International Phase III study comparing 
abiraterone acetate, given at 1000 mg once daily with prednisone 5 mg BID to placebo and 
prednisone 5 mg BID in men with mCRPC previously treated with docetaxel-based 
chemotherapy [22].  Overall survival was the primary endpoint and 1195 patients were 
enrolled.  A planned interim analysis after 534 patients met the primary endpoint revealed a 
statistically significant difference in overall survival between the abiraterone acetate and 
prednisone arm (median OS 14.8 months; 95% CI 14.1- 15.2) and the placebo and prednisone 
arm (median OS 10.9 months; 95% CI 10.2-12.0) with a hazard ratio of 0.646 and a p < 0.0001 
[22]. Secondary endpoints were all statistically significant in favor of abiraterone acetate 
including time to PSA progression, radiographic progression, and PSA response.  Subgroup 
analysis revealed all parameters in favor of abiraterone acetate.   Side effects in this large phase 
III heavily pre-treated population were relatively low and balanced in both arms except for fluid 
retention, hypokalemia, hypertension and cardiac disorders; however, grade 3 or greater 
incidence of these toxicities were less than 5%.  These results have led to the FDA-approval of 
abiraterone acetate with prednisone for patients with mCRPC who have failed docetaxel-based 
chemotherapy.   
 
In chemotherapy-naïve mCRPC, the COU-AA-302 study was a randomized, double blind, 
international phase III study comparing abiraterone acetate and prednisone to placebo and 
prednisone [23]. 1088 patients were randomized in a 1:1 ratio and treated until radiographic 
progression.  Radiographic progression-free survival and overall survival were co-primary 
endpoint.  Three interim analyses were pre-planned.  At the time of the second interim 
analysis, following after 311 events (43% of events) the independent data safety monitoring 
committee recommended halting the study and unblinding the patients due to a statistically 
significant positive effect in favor of abiraterone acetate for radiographic progression-free 
survival (HR 0.43; 95% CI 0.35-0.52; p < 0.0001), a strong trend in favor of overall survival  (HR: 
0.75; 95% CI 0.61-0.93; p = 0.0097) and positive secondary endpoints as well [23].  A final 
analysis confirmed a statistically significant clinical benefit in median overall survival in favor of 
abiraterone acetate with prednisone (34.7 months [95% CI 32.7-36.8] vs 30.3 months [28.7-33.3]; 
hazard ratio 0.81 [95% CI 0.70-0.93]; p=0.0033) [86]. These results led to the FDA-approval of 
abiraterone acetate with prednisone for patients with mCRPC in December 2012.    
 
For the most comprehensive clinical information regarding the efficacy and safety of 
abiraterone acetate, refer to the latest version of the Package Insert for abiraterone acetate.  
 
4.2 
APALUTAMIDE  
 
Apalutamide has been approved by the US Food and Drug Administration (FDA) for the 
treatment of non-metastatic castration resistant prostate cancer and metastatic castration-
sensitive prostate cancer, but not for metastatic castration resistant prostate cancer.  It is a 

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competitive AR inhibitor developed to optimally antagonize AR transcriptional activity and 
prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy [81]. In contrast to 
bicalutamide, apalutamide lacks significant agonist activity in preclinical models of CRPC. 
Moreover, apalutamide does not induce AR nuclear localization or DNA binding. In a clinically 
valid murine xenograft model of human CRPC, apalutamide showed greater efficacy than 
MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of 
apalutamide, whereas the same response required 100 mg/kg/d of MDV3100 and higher 
steady-state plasma concentrations. Thus apalutamide exhibits characteristics predicting a 
higher therapeutic index with a greater potential to reach maximally efficacious doses in man 
than current AR antagonists. Our findings offer preclinical proof of principle for apalutamide as 
a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate 
cancer. 
In Phase I testing apalutamide was dosed between 30 mg and 480 mg once daily, resulting in 
PSA declines at all dose levels and a median 50% decline from baseline PSA at 12 weeks of 47% 
[82].  The most frequently reported adverse event was grade 1/2 fatigue (47%). A phase II 
multicenter study evaluated the clinical efficacy of apalutamide at 240 mg daily in non-
metastatic (nm) CRPC patients.  In 51 evaluable patients 89% had ≥50% PSA decline at 12 
weeks. Median time to PSA progression was 24.0 mo (95% confidence interval [CI], 16.3 months 
- not reached [NR]); median metastasis-free survival was NR (95% CI, 33.4 months - NR). The 
most common AE was fatigue (any grade, n=31 [61%]) [83]. A Phase III Study of apalutamide 
versus placebo in men with nmCRPC has showed that apalutamide prolonged metastasis-free 
survival and time to symptomatic progression. [89] 
Additional details of the preclinical and clinical testing of apalutamide conducted thus far can 
be found in the apalutamide investigator’s brochure or package insert. 
 
 
4.3 
Rationale 
 
African American men have a 60% greater incidence of being diagnosed with prostate cancer 
and nearly a 2.5 fold greater chance of mortality from the disease, yet the underlying cause for 
this increased mortality remains controversial [24].  Hormonal levels vary in men by race, with 
African American men having higher dihydrotestosterone (DHT), androstenedione (ASD) and 
sex hormone-binding globulin (SHBG) than Caucasian men with localized prostate cancer [5, 
25]. Historically, African American men with prostate cancer have a worse overall survival than 
Caucasian men, however, this is confounded by the timing of androgen deprivation therapy 
(ADT) and access to other therapies [26, 27].  To what extent race affects response to therapy in 
prostate cancer is not clear.    

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Germline polymorphisms of genes involved in androgen signaling have been shown to vary 
significantly by race and may have important implications with regard to response to therapy 
targeted towards this pathway. Polymorphisms within the promoter region of the androgen 
receptor (AR) (specifically CAG repeats) have been well documented and vary significantly 
according to race, with African American men having significantly shorter CAG repeats resulting 
in greater AR activity [28].  These CAG repeats have been associated with more aggressive 
disease characteristics [28].  Recently, germline polymorphisms in androgen metabolism genes 
have been shown to have prognostic value in regards to the time to development of CRPC in 
men with prostate cancer on ADT.  Ross et al tested 129 polymorphisms across 20 genes 
associated with androgen metabolism and identified three polymorphisms in separate genes 
(CYP19A1, HSD3B1, and HSD17B4) that were significantly associated with prolonged time to 
progression (TTP) on ADT [29].  Specifically, individuals carrying more than one of the 
polymorphisms were associated with improved time to CRPC than individuals carrying zero or 
one (P< .0001).  More recently this group identified polymorphisms in two androgen 
transporter genes, SLCO2B1 and SLCO1B3 that were associated with a significantly shorter time 
to CRPC alone and in combination [30].  Incidences of these polymorphisms ranged from 15 to 
81%; unfortunately, the cohort of patients used to identify these polymorphisms had limited 
numbers of African American patients or other racial and ethnic groups.   
Recent studies by our laboratory and others have focused on discovering molecular 
mechanisms underlying prostate cancer disparities using microarrays and bioinformatics.  These 
studies have compared the gene expression profiles between African American and Caucasian 
cancers and between prostate cancer and patient-matched normal prostate from African 
American and Caucasian.  By integrating gene expression profiling and pathway analyses, 
multiple components within the androgen receptor signaling pathway were revealed to be up-
regulated in African American prostate cancer specimens along with the up-regulation of genes 
within other signaling pathways that converge on androgen receptor signaling, portending that 
androgen receptor pathway activation is a key component of prostate cancer health disparities.  
Overall the comparison of African American and Caucasian prostate cancer specimens has led 
to the identification of a number of differentially expressed genes, including CYP19A1, AMFR, 
CXCR4, MMP9, SRD5A2, ADIPOQ, AKT1, ALOX12, ALOX15, ALOX15B, BMP2, CGA, ERG, FASN, 
IL1B, IL6, IL8, NFKB1, PIK3C3, PIK3CA, PI3K3R1, PLA2G2A, TGFB1, TIMP3, TNF, P38MAPK, STAT1, 
RHOA, ITGB5, MAPKAPK2, CSNK2A1, PIK3CB, ARA55, GNA01, GNB3, POLR2L, PRKCE, PRKD1, 
TBP, CALR, GNG2, GNG11, GNG12, CALM1, NFKB2, STAT2, RHOU, FGF13, EIF3B, and GIT1 [31-
34].  Thus, germline polymorphisms of these differentially expressed genes also may have 
important implications with regard to response to therapy targeted towards the androgen 
signaling pathway.  In addition, our laboratory has identified a number of novel alternatively 
spliced genes in African American versus Caucasian prostate cancer and have shown that 
African American variants track with more aggressive cancer invasion characteristics of prostate 
cancer in African American men (Bi-Dar Wang, Jennifer A. Freedman, Daniel J. George, Norman 
H. Lee and Steven R. Patierno, manuscript in preparation).  Moreover, we have identified novel 

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single nucleotide polymorphisms located in splicing regulatory regions of such genes that 
associate with prostate cancer risk, aggressiveness and survival (Jennifer A. Freedman, Yanru 
Wang, Hongliang Liu, Patricia G. Moorman, Terry Hyslop, Daniel J. George, Norman H. Lee, 
Qingyi Wei and Steven R. Patierno, manuscript in preparation).  Subsets of these genes are 
androgen receptor targets.  Therefore, germline polymorphisms of these alternatively spliced 
genes also may have important implications with regard to response to therapy towards the 
androgen signaling pathway. 
To what extent racial differences affect response and time to progression on secondary 
hormonal therapies in the CRPC setting are unknown.  A retrospective analysis of the COU-AA-
302 study included only 28 black patients but demonstrated trends in favor of median rPFS and 
90% decline from baseline PSA in this subpopulation vs the entire population [79]. Similarly, a 
retrospective case-controlled analysis of patients treated at Duke University with abiraterone 
prednisone pre or post docetaxel chemotherapy revealed statistically significant improved PSA 
response rate in African American vs Caucasian patients by 30% decline (77.8% vs 54.4%; 
p=0.008) and 50% decline (68.9% vs 48.9%; p=0.028) with trends in favor of 90% PSA decline 
(37.8%, vs. 28.9%) [80]. In addition, primary abiraterone-refractory disease (PSA increase as 
best response) trended to be more in Caucasian than in African American patients (31.1% vs 
15.6%; p=0.052).   Based upon these findings we hypothesized that African American CRPC 
patients may be more sensitive to abiraterone acetate with prednisone than Caucasian 
patients.  We have conducted a prospective Phase II study of abiraterone acetate with 
prednisone in patients with mCRPC, stratified by self-described race in order to test this 
hypothesis (Abi Race Clinicaltrials.gov NCT01940276).  Secondarily, to what extent differences 
in systemic hormonal levels as well as androgen transport gene polymorphisms affect response 
to abiraterone acetate is unknown. Understanding any potential differences in response to 
therapy by race and/or by hormonal/genetic factors could impact on both our clinical use of 
abiraterone acetate as well as future clinical trial design. Finally, as other agents targeting the 
androgen/androgen receptor pathways become available, it will be important to differentiate 
their activity according to race, genetics and hormonal milieu.   
The concept of combining apalutamide with abiraterone acetate and prednisone derives from 
their potentially complimentary mechanisms of action in which apalutamide functions as a pure 
androgen receptor antagonist while abiraterone acetate inhibits cholesterol metabolism into 
androgen, thus lowering the functional levels of ligand for the receptor.  Since most patients 
who progress on abiraterone acetate do so with a rising PSA we believe the androgen receptor 
remains a driver of disease progression in patients treated with abiraterone acetate and 
prednisone alone.  Together, these apalutamide and abiraterone acetate may be able to more 
completely inhibit the androgen – androgen receptor axis and provide greater clinical benefit.  
An ongoing Phase III study (ACIS) is evaluating whether the combination of apalutamide, 
abiraterone acetate and prednisone improves radiographic progression-free survival compared 
to abiraterone acetate, prednisone and placebo (clinicaltrials.gov NCT02257736). Like the COU-
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African American patients, leaving unanswered the question of whether African American 
patients may have a genetic propensity for response and clinical benefit to this combination.  
We propose a Phase II open label, prospective study to evaluate, radiographic PFS in men with 
mCRPC stratified by self-described race and treated with apalutamide, abiraterone acetate and 
prednisone. Secondary endpoints will describe the response to apalutamide, abiraterone 
acetate and prednisone, PSA kinetics, pharmacokinetics of abiraterone acetate as well as safety 
and tolerability. Exploratory endpoints will describe the incidence and associations of key 
hormonal levels as well as germline polymorphisms in androgen signaling genes and genes that 
have been shown to be differentially expressed in African American versus Caucasian prostate 
cancers in both African American and Caucasian cohorts.  
 
5. 
STUDY OBJECTIVES AND ENDPOINTS 
 
5.1 
Study objectives 
 
5.1.1 
Primary objective 
 
The primary goal is to estimate the radiographic PFS distribution of African American and 
Caucasian men with mCRPC treated with apalutamide, abiraterone acetate, and prednisone. 
 
5.1.2 
Secondary objectives 
 
1) PSA kinetics: to determine  the duration of PSA response, time to nadir, and percent of men 
who achieve a PSA < 0.1 ng/mL;  
2) Radiographic assessments: to estimate the rate of objective response and incidence of bone 
flares 
3) Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension in 
the two populations  
4) Overall survival  
 
5.1.3 
Exploratory objectives 
1) Perform ancestral genotyping to obtain genetically estimated indicators of race using DNA 
isolated from whole blood at baseline. 
2) Describe the baseline profile of serum hormone levels (including but not limited to 
testosterone, DHT, DHEA, DHEAS, estradiol) and lipids, the change in levels with 
subsequent therapy (Cycle 4), and their correlation with response to abiraterone acetate 
plus apalutamide.   
3) Abiraterone Pharmacokinetics (PKs) drawn at cycle 1 d1 at 1, 2, 4, 8 hours post dose and 
cycle 2 d1 at  (24 hour trough), 1, 2, 4, 8 hours post dose.  

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4) Describe the germline SNP profiles of the androgen receptor gene, target genes involved in 
androgen metabolism and signaling and target genes that have been shown to be 
differentially expressed in African American versus Caucasian prostate cancer and their 
associations with response to abiraterone acetate plus apalutamide. The status of the 
aforementioned targets will also be assessed in archival tumor tissue, if available. 
5) Describe the expression and splicing profiles of the androgen receptor gene, target genes 
involved in androgen metabolism and signaling and target genes that have been shown to 
be differentially expressed and/or spliced in African American versus Caucasian prostate 
cancer and their associations with response to abiraterone acetate plus apalutamide. The 
status of the aforementioned targets will also be assessed in archival tumor tissue, if 
available. 
6) Describe cell-free plasma DNA profiles and their associations with response to abiraterone 
acetate plus apalutamide. 
7) To explore the associations between baseline levels and treatment-related changes of 
plasma-based protein markers with response in patients treated with abiraterone acetate 
plus apalutamide. 
8) Describe abiraterone metabolism by race with particular attention to active metabolites 
including D4A and 3-keto-5α-abiraterone. 
9) To assess the concordance between the genomic alterations identified in cfDNA to the 
genomic alterations identified in the tumor-derived DNA 
 
5.2 
Study endpoints 
 
 
5.2.1 
Primary endpoint 
 
The primary endpoint will be radiographic progression free survival (rPFS) based on modified 
PCWG3 criteria or based on the onset of a skeletal related event.  Imaging will be obtained 
every 12 weeks. 
 
5.2.2 
Secondary endpoints 
 
Secondary endpoints will include: 
1) PSA kinetics: to determine  the duration of PSA response, time to nadir, and percent of 
men who achieve a PSA < 0.1 ng/mL;  
2) Radiographic assessments: to estimate the rate of objective response and incidence of 
bone flares 
3) Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension 
in the two populations  
4) Overall survival  
 

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5.2.3 
Exploratory correlative sciences endpoints 
 
Whole blood will be collected in purple top EDTA tubes at baseline for DNA isolation.  Isolated 
DNA will be used for ancestral genotyping to obtain genetically estimated indicators of race and 
for characterization of SNPs of androgen metabolism and signaling genes as well as genes that 
have been shown to be differentially expressed in African American versus Caucasian prostate 
cancer. A genome wide association study (GWAS) is planned in both African American and 
Caucasian men with mCRPC and their association with response to abiraterone acetate plus 
apalutamide, in line with the specified endpoints and biomarkers defined in the trial. In 
addition, blood will be collected in PAXgene Blood RNA Tubes at baseline, cycle 4, and at 
progression or end of treatment for RNA isolation and characterization of differential 
expression and/or splicing of the androgen receptor gene, TMPRSS2-ERG gene fusion, androgen 
metabolism and signaling genes and genes that have been shown to be differentially expressed 
and/or spliced in African American versus Caucasian prostate cancer. Blood will also be 
collected at baseline, cycle 2 and at progression or end of treatment in EDTA vacutainers for 
cell-free plasma DNA isolation and characterization. Moreover, baseline assessments of 
lipidomics and hormonal levels, including but not limited to testosterone, DHT, DHEA, DHEAS 
and estradiol and their change after 12 weeks on therapy will be evaluated from collected 
serum. Furthermore, abiraterone pharmacokinetics (PKs) will be drawn on day 1 and day 29 
(C2d1) at 24 hour trough, 1, 2, 4 and 8 hours post dose of study drug.  Finally, baseline, Cycle 2 
and at progression or end of treatment in EDTA vacutainers will be drawn to explore additional 
circulating protein biomarkers that may have prognostic or predictive value. In addition to 
blood, formalin-fixed, paraffin-embedded archival tumor tissue will be collected whenever 
available from all patients having undergone a diagnostic core biopsy or a surgery 
(prostatectomy or metastatic sampling). 
 
6. 
INVESTIGATIONAL PLAN 
 
6.1 
Overall study design 
 
This is a phase II open-label, multicenter study of apalutamide, abiraterone acetate and 
prednisone in African American and Caucasian men with mCRPC. The primary goal is to 
prospectively estimate the median radiographic PFS in African American and Caucasian men 
with mCRPC cancer treated with apalutamide and abiraterone acetate. Patients will self-report 
on race and 50 patients will be enrolled into each group.  Patients will be treated on open-label 
treatment until evidence of disease progression as defined by Prostate Cancer Working Group 
Three (PCWG3) modified definition [35] or until two years at which point they will roll over to 
the standard of care at that time.   
 
Study schema is shown below. 

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4. Written Authorization for Use and Release of Health and Research Study Information 
(HIPAA authorization per institutional requirements) 
5. Willing/able to adhere to the prohibitions and restrictions specified in this protocol  
6. Willing to take abiraterone acetate on an empty stomach, and should be able to swallow 
tablets whole, without crushing/chewing tablets. Must have the ability to swallow, 
retain, and absorb oral medication. 
7. Medications known to lower the seizure threshold (see list under prohibited meds, 
appendix 2) must be discontinued or substituted at least 4 weeks prior to study entry 
8. 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 after receiving the last dose of study drug.  
Abstinence is an acceptable method of birth control. 
9. Adequate bone marrow function as shown by: ANC ≥ 1.0 x 109/L, Platelets ≥ 100 x 109/L, 
Hb≥9 g/dL, (independent of transfusion and/or growth factors within 3 months prior to 
Cycle 1 Day 1) 
10. Serum potassium ≥ 3.5 mEq/L  
11. Serum albumin of ≥ 3.0 g/dl 
12. AST/SGOT and ALT/SGPT <2.5 x Institutional Upper Limit of Normal (ULN)  
13. Serum total bilirubin ≤ 1.5 x Institutional 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) 
14. GFR ≥30 mL/min  
15. Confirmation of diagnosis of adenocarcinoma of the prostate through either histological 
methods or tissue, or diagnosis clinically consistent with prostate cancer. Histologic 
variants of prostate cancer comprising of >50% of the tumor including neuroendocrine 
features and small cell carcinoma of the prostate are excluded 
16. Radiographic evidence of metastatic disease based on RECIST 1.1 Criteria OR by prostate 
cancer-specific PET imaging.  Evaluable non-target lesions and/or bone only metastasis 
are permitted per RECIST 1.1 and PCWG3 guidelines. Non-target, pathological lymph 
nodes ≥ 10 mm and less than 15 mm in the short axis are permitted. 
17. Ongoing ADT using an LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g. 
degarelix) must continue on therapy unless prior bilateral orchiectomy has been 
performed.   
18. PSA ≥ 2.0 ng/mL  
19. Evidence of castration resistant disease in the setting of ongoing ADT (medical or 
surgical) as evidenced by at least one of the following: 
• Absolute rise in PSA of 2.0 ng/mL or an increase >25% from the nadir, minimum 2 
consecutive rising PSA levels with an interval of ≥ 1 week between each PSA level, 
OR 
• CT or MRI based evidence of disease progression (soft tissue, nodal or visceral 
disease progression)  according to RECIST 1.1 criteria, OR  

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• At least 1 new bone scan lesion as compared to the most immediate prior radiologic 
studies. 
20. A minimum of 2 weeks elapsed off of antiandrogen therapy prior to start of study drug 
(i.e. flutamide, nilutamide, bicalutamide.) 
21. A minimum of 2 weeks elapsed off of sipuleucel-T and radiation therapy prior to start of 
study drug   
22. A minimum of 4 weeks from any major surgery prior to start of study drug.   
23. Self-reported race of either African American/Black or Caucasian.  
24. Ability to understand and the willingness to sign a written informed consent document. 
If the subject is unable to understand the consent due to comorbidity, such as 
Alzheimer’s disease, consent by a legally authorized representative and assent by the 
subject will be obtained.  
 
Exclusion Criteria:   
1. Prior treatment with abiraterone acetate, enzalutamide, apalutamide, galaterone (TOK-
001), orteronel (TAK-700), or similar agent 
2. Active infection or other medical condition that would make prednisone/prednisolone 
(corticosteroid) use contraindicated 
3. Active or symptomatic infection including HIV, viral hepatitis or chronic liver disease 
4. Any chronic medical condition requiring a higher dose of corticosteroid than 5mg 
prednisone/prednisolone bid 
5. Have known allergies, hypersensitivity, or intolerance to abiraterone acetate, 
apalutamide or prednisone or their excipients.  
6. Pathological finding consistent with small cell carcinoma of the prostate 
7. Symptomatic liver or visceral organ metastasis 
8. Have a history of gastrointestinal disorders (medical disorders or extensive surgery) that 
may interfere with the absorption of the study agents 
9. Known brain metastasis   
10. Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC. Note: 
sipuleucel-T is permitted with a 2-week washout.  
11. Previously treated with ketoconazole for prostate cancer for greater than 7 days  
12. Prior systemic treatment with an azole anti-fungal drug (e.g. fluconazole, itraconazole) 
within 4 weeks of Cycle 1, Day 1. 
13. Uncontrolled hypertension (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg). 
Patients with a history of hypertension are allowed provided blood pressure is 
controlled by anti-hypertensive treatment 
14. Poorly controlled diabetes, FBS ≥200 mg/dL 
15. History of pituitary or adrenal dysfunction 
16. Symptomatic Atrial Fibrillation, or other symptomatic cardiac arrhythmia 
17. Other malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of 
recurrence within 24 months 
18. History of any of the following: 

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• Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 
6 months of Cycle 1 Day 1, brain arteriovenous malformation, Schwannoma, 
meningioma, or other benign CNS or meningeal disease which may require 
treatment with surgery or radiation therapy) 
• Severe or unstable angina, myocardial infarction, symptomatic congestive heart 
failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, 
cerebrovascular accident including transient ischemic attacks), or clinically 
significant ventricular arrhythmias within 6 months prior to first dose of study drug.  
Venous thrombolic events within 6 months are permitted IF they are not attributed 
to prostate cancer (in the opinion of the treating physician). 
19. Baseline administration of concomitant strong CYP3A4 inducers and planned to 
continue during abiraterone acetate treatment.  
20. Baseline administration of and planned co-administration of abiraterone acetate with 
CYP2D6 substrates that have a narrow therapeutic index. If an alternative treatment 
cannot be used, exercise caution and consider a dose reduction of the concomitant 
CYP2D6 substrate 
21. Baseline moderate or severe hepatic impairment (Child Pugh Class B & C) 
22. Use of herbal products that may decrease PSA levels (i.e., saw palmetto) refer to section 
8.3.2 (no washout period required) 
23. Administration of an investigational therapeutic within 30 days prior to Cycle 1, Day 1 
24. Any condition which, in the opinion of the investigator, would preclude participation in 
this trial 
 
7. 
PATIENT REGISTRATION 
After signing informed consent and completing eligibility screening, patients who are selected 
to participate will be registered with the lead site (Duke) and with their study site/institution.  A 
record of patients who fail to meet entry criteria (i.e., screen failures) will be maintained.  
Patient registration must be complete before beginning any treatment.  
 
7.1 
Informed Consent 
Authorized study personnel should fully explain the scope of the study to each patient before 
obtaining informed consent.  If the patient is not able to fully understand the informed consent 
due to a known comorbidity, such as Alzheimer’s disease, a legally authorized representative 
will be included in the consent process. Patients, and a legally authorized representative if 
appropriate, should be advised of any known risks inherent in the planned procedures, of any 
alternative treatment options, of their right to withdraw from the study at any time for any 
reason, and of their right to privacy. If a legally authorized representative signs the consent, the 
patients’ assent will also be documented. 
 
When obtaining informed consent, study personnel should: 
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Next: Obtain dated and signed informed consent. 
Finally: Confirm that the patient is eligible as defined in Section 6.3 (Inclusion/Exclusion 
Criteria).  A record of patients who fail to meet entry criteria (i.e., screening failures) will 
be maintained. 
For patients consented at the lead site ONLY, registration in the Duke clinical trial subject 
registry must be completed within 1 business day of the patient providing informed consent. 
 
7.2 
Lead Site Registration 
Patient registration for all patients signing informed consent will be completed by Duke 
University Genitourinary Oncology Group. Following consent and completion of the Eligibility 
Checklist, de-identified documents will be submitted for review and registration of subject. All 
subjects will be assigned a unique study ID.  
 
Refer to Subject Registration Instructions for details.  See coordinator manual. 
 
Patients will be enrolled only after all pre-treatment screening evaluations are completed and 
all eligibility criteria are met. Once the patient has signed consent and been found to meet all 
eligibility criteria, the subject will be registered. The date of enrollment is the date the patient 
starts study drug. A unique patient study identification number will be assigned by the enrolling 
site upon consenting.  This number will include the site # and subject number such as 01-001. 
01 being the site number and 001 being the first subject enrolled at that site. The numbers will 
be assigned sequentially and include all subjects that are consented.  Minimal amount of 
information will be entered into the database for subjects that consent but do not enroll.  
Treatment must not commence until the study team has received the approved documentation 
from the lead site. Treatment will commence according to the guidelines in the protocol.  
Should a patient present on Cycle 1 Day 1 with an adverse event that is in conflict with the 
eligibility criteria, the subject may be treated for the adverse event and started on study drug as 
scheduled per the treating provider’s discretion.  The event must be reviewed and approved by 
the Sponsor-Investigator prior to starting therapy. 
7.3 
Institutional Registration 
Patient registration at each study site/institution will be conducted according to the 
institution’s established policies.  Prior to registration, patients will be asked to sign and date an 
Institutional Review Board (IRB)-approved consent form.  Patients must be registered with their 
local site/institution and with the lead site before beginning any treatment or study activities.  

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8. 
TREATMENTS 
8.1 
Abiraterone acetate  
8.1.1 
Abiraterone acetate Formulation 
Abiraterone acetate 250-mg tablets are oval, white to off-white and contain abiraterone 
acetate and compendia (USP/NF/EP) grade lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, colloidal 
silicon dioxide, and purified water, in descending order of concentration (the water is 
removed during tableting). 
8.1.2 
Handling abiraterone acetate tablets 
This medicine may cause harm to the unborn child if taken by women who are pregnant. It 
should not be taken by women who are breast-feeding. Women who are pregnant or who may 
be pregnant should wear gloves if they need to touch abiraterone acetate tablets. You should 
notify any caregivers and staff personnel of this information, to ensure the appropriate 
precautions are taken. 
 
8.1.3 
Abiraterone acetate administration 
The study agent abiraterone acetate will be administered by the patient at a dose of 1000mg 
orally once daily with prednisone 5 mg BID in 4-week cycles throughout the treatment period.  
Abiraterone acetate must be taken on an empty stomach. No food should be consumed for at 
least one hour before the dose of abiraterone acetate is taken and for at least two  hours after 
the dose of abiraterone acetate is taken. Abiraterone acetate should be taken with a glass of 
water and consumed over as short a time as possible.  Patients should swallow the tablets 
whole and not chew them.  Study drug will be provided by Janssen Scientific Affairs and 
distributed by DCI Investigational Chemotherapy Service, which will be distributing drug to the 
satellite sites. Study drug should at all times be kept in the original packaging. 
 
Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, 
respectively, when a single dose of abiraterone acetate was administered with a meal 
compared to a fasted state. The safety of these increased exposures when multiple doses of 
abiraterone acetate are taken with food has not been assessed. 
 
Patients will be instructed to take a 5mg prednisone tablet, twice daily with food.  It is not 
required for the prednisone to be taken at the same time as abiraterone acetate. The dose of 
prednisone will remain unchanged in the event that the study drug dose is changed. If a 
prednisone dose is missed, it should be omitted and will not be made up. Should a dose 
modification of the prednisone be needed due to toxicities, the site will need to discuss this 
with the Sponsor-Investigator. 
 

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Each treatment cycle consists of 28 consecutive days. No cycle will be delayed.  If doses of study 
drug are held or missed, they will not be made up. The subject could complete a maximum of 
26 cycles during the 24 month duration of the study.  Patients may take apalutamide with 
abiraterone acetate plus prednisone until radiographic disease progression (as defined in 
Section 12.5); at which time study treatment will be discontinued.  
 
If vomiting occurs during the course of treatment, no redosing of the patient is allowed before 
the next scheduled dose. If > 6 hours after the subject’s regularly scheduled dose then the dose 
should be withheld that day and abiraterone acetate should be restarted the following day. 
 
8.1.4 
Effects of Abiraterone Acetate on Drug Metabolizing Enzymes 
Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a 
CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 
substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given 
with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-
administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic 
index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and 
consider a dose reduction of the concomitant CYP2D6 substrate drug. 
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 
substrate) was increased by 46% when pioglitazone was given together with a single dose of 
1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of 
toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly 
with abiraterone acetate. 
 
Drugs that Inhibit or Induce CYP3A4 Enzymes 
 
Based on in vitro data, abiraterone acetate is a substrate of CYP3A4.  In a clinical 
pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer 
(rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1000 mg, 
the mean plasma AUC∞ of abiraterone was decreased by 55%. 
 
Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 
phenobarbital) during treatment with abiraterone acetate are to be avoided, or used with 
careful evaluation of clinical efficacy. 
 
In a separate clinical pharmacokinetic interaction study of healthy subjects, coadministration of 
ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the 
pharmacokinetics of abiraterone. 
 

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All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded.  If a patient requires an abiraterone acetate or apalutamide dose delay of >21 
days from the previous dose or 28 days in cases of rash, the patient must be discontinued from 
treatment (unless unrelated to study drug and approved by the Sponsor-Investigator) with the 
delayed drug but remain on study for other study treatments as planned.   
 
Medication labels will comply with US legal requirements and be printed in English. Labels of 
subjects at Duke will include their name and medical record number.   External sites will include 
information according to their institutional guidelines. The storage conditions for study drug 
will be described on the medication label. 
 
8.2 
Apalutamide   
Apalutamide has been approved by the FDA for the treatment of nonmetastatic castrate 
resistant prostate cancer  and metastatic castration-sensitive prostate cancer at a dose of 240 
mg. Apalutamide has not been approved by the FDA for metastatic castration resistant prostate 
cancer and, consequently, is investigational in the context of this study.  
Tablets: The apalutamide drug substance is an almost white to slightly brown powder that is 
formulated in tablets at a strength of 60 mg. 
Apalutamide is administered orally on a continuous once daily dosing schedule. Each cycle of 
drug administration consists of 28 days. Doses from 30 to 480 mg were tested in the Phase 1 
portion of the first clinical study (Study ARN-509-001). The therapeutic dose is 240 mg once 
daily. Apalutamide can be taken with or without food. 
 
8.2.1 
Apalutamide Tablets 
Apalutamide tablets (60 mg) are packaged in 120-count bottles, and should at all times be kept 
in the original packaging. 
Detailed information on handling and storage conditions will accompany the clinical drug 
supplies to the clinical study site(s). The storage conditions and expiry will be indicated on the 
label of the drug product. 
 
8.2.2 
Apalutamide Pharmacology 
The mechanism of action of apalutamide is through antagonism of the androgen receptor and 
inhibition of AR nuclear translocation and DNA binding to AREs. Unlike bicalutamide, 
apalutamide shows no significant agonist properties in a model of CRPC 
(e.g., AR-over-expressing prostate cancer cells; LNCaP/AR cells). Gene transcription of PSA and 
TMPRSS2 is inhibited by apalutamide and results in concentration-dependent reduction of 
these protein levels in vitro. Apalutamide was also shown to reduce proliferation of CRPC cells 
as well as increase apoptosis and necrosis in vivo. These effects are supported by the anti-
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dose-dependent tumor growth inhibition and tumor regression over a dose range of 0.1 to 
10 mg/kg/day, with effects that were superior to bicalutamide. 
   
8.3 
Concomitant therapy 
 
All medications (excluding prior chemotherapy and biologic, immunologic or radiation therapy) 
taken within 4 weeks prior to the administration of apalutamide and abiraterone acetate and 
all concomitant therapy administration during the study with reasons for therapy should be 
recorded.   
Patients on chronic medications that can be given concomitantly with apalutamide and 
abiraterone acetate should be maintained on the same dose and dose schedule throughout the 
study period, as medically feasible.  The investigator should instruct the patient to notify the 
study site about any new medications he takes after the start of the study drug.  All new 
medications, changes in medication dosing, and significant non-drug therapies (including herbal 
medicines, physical therapy and blood transfusions) administered after the patient starts 
treatment with study drug and 30 days after end of treatment will be recorded in the database 
(during the safety follow up period).  
 
8.3.1 
Permitted Concomitant Medications  
 
The following concomitant medication/therapies are permitted if deemed necessary for the 
care of the patient:  
• Standard therapies for preexisting conditions, medical/surgical complications 
including nausea and diarrhea, and palliation. 
• Non-potent CYP3A4 isoenzyme inhibitors and/or inducers. 
• LHRH agonists or antagonists. 
• Anti-hypertensive medications. 
• Diabetic medications. 
• Antidepressants or other medications for mood disorders.   
• Analgesics including opioids. 
• Bisphosphonates and/or denosumab. 
• Erythropoietic agents. 
• Systemic anticoagulation with low molecular weight heparin. 
• Focal therapies for localized non-prostate cancers 
• Provenge, after the first 3 cycles on treatment are completed.  
 
8.3.2 
Prohibited Concomitant Medications  
• Other investigational therapies must not be used while the patient is on the study. 
• Site pharmacist or physician should review subject’s concomitant medication list while 
subject is in screening and once enrolled on study, for any drug interaction.  

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• Chemotherapy, radiation therapy, or immunotherapy, or any anti-cancer therapy other 
than apalutamide and abiraterone acetate and prednisone and those described above or 
below. 
• Herbal preparations/medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.  
Patients should stop using these herbal medications, with no washout delay required prior 
to first dose of study drug. 
• In lieu of surgical castration, the use of an LHRH agonist or antagonist must continue while 
on this study.  However, antiandrogens, ketoconazole, estrogens, and all other forms of 
hormonal manipulation are not permitted for the treatment of cancer. 
• Investigators should keep in mind the possibility that abiraterone acetate may interact with 
concomitant medications, particularly those that are metabolized or activated by P450 
CYPs 2D6 and 1A2 (see Appendix 2 for a list of such medications to be used with caution).    
Please see comments above regarding interactions.  If at any time an investigator suspects 
a drug-drug interaction due to abiraterone acetate therapy, an adverse event report should 
be completed and Duke University notified. 
• Immunosuppressive doses of systemic corticosteroids greater than prednisone 5 mg twice 
daily or the equivalent. Short term use of systemic corticosteroids are allowed for side 
effect management with notification to the Sponsor-Investigator.  
• As a class effect, AR antagonists have been associated with seizures due to an off-target 
mechanism of action (gamma amino butyric acid chloride channel [GABAA] inhibition). 
Drugs known to lower the seizure threshold or cause seizures are prohibited. See appendix 
2.A  representative list is included below:  
• Atypical antipsychotics (e.g. clozapine, olanzapine, risperidone, ziprasidone) 
• Bupropion 
• Lithium 
• Meperidine and pethidine 
• Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine) 
• Tricyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, imipramine, 
maprotiline, mirtazapine 
8.3.3 
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 (see Appendix 2 for a list 
of these medications to be used with caution). 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:  
• 
Strong CYP3A4 inhibitors: itraconazole, clarithromycin, erythromycin, diltiazem, verapamil, 
delavirdine, 
atazanavir, 
indinavir, 
nefazodone, 
nelfinavir, 
ritonavir, 
saquinavir, 

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telithromycin, voriconazole, grapefruit juice (or grapefruits); co-administration with any of 
these agents may increase apalutamide plasma concentrations 
• 
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 
The potential for drug-drug interaction between apalutamide and warfarin (e.g., Coumadin) is 
unknown at present. If a subject is taking warfarin, re-assess PT (prothrombin time) 
/international normalized ratio (INR) as clinically indicated and adjust the dose of warfarin 
accordingly. 
Based on in vitro data, abiraterone acetate is a substrate of CYP3A4. In a dedicated drug 
interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of 
abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during abiraterone acetate 
treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone 
acetate  dosing frequency. In a dedicated drug interaction trial, co-administration of 
ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the 
pharmacokinetics of abiraterone. Abiraterone acetate is an inhibitor of the hepatic drug-
metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax 
and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, 
respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and 
prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of 
CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be 
used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate 
drug. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone 
(CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single 
dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs 
of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used. 
8.4 
Treatment compliance 
 
Participating sites will be provided with a medication diary for each patient to document his 
self-administration of apalutamide, abiraterone acetate, and prednisone per cycle.  A current 
and accurate account of the number of study treatment tablets the investigator received from 
Duke University, dispensed to the patients, the number of units returned to the investigator by 
the patient, and the number of units returned to Duke University during and at the completion 
of the study must be maintained.  A detailed inventory must be completed for the study 
treatment. Records of study medication used, dosages administered, and intervals between 
visits will be recorded during the study.  Drug accountability will be noted and patients will be 
asked to return all unused study medication. 
 
 
 

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9. 
STUDY ASSESSMENTS 
9.1 
Vital signs, performance status, and physical exam 
 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight per the visit schedule.   
 
The patient will be asked to check his blood pressure at home at least monthly between clinic 
appointments and notify the coordinator of elevated blood pressures grade 2 and above.  This 
will be recorded on the medication diary provided to the patient and collected at the end of 
each cycle. Elevated blood pressure readings should be confirmed with a second reading taken 
after the patient has rested. 
 
 
Performance status will be assessed at screening and per the visit schedule using the Karnofsky 
performance status scale (Appendix 1).  
 
Physical examination will comprise a total body examination (general appearance, skin, 
including eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and 
basic nervous system).  Significant findings made after the start of study drug which meet the 
definition of an Adverse Event must be recorded. 
 
9.2 
Laboratory evaluations 
 
The following laboratory studies will be obtained at specified intervals to assess subject safety, 
specifically the risk of infection, hyperglycemia, thyroid and/or bone marrow, liver, and kidney 
abnormalities.  Abnormalities will be captured as AEs only if deemed clinically significant by the 
treating physician/provider/investigator.   
• Hematology:   Complete blood count (CBC) consisting total white blood cell count (WBC) 
with differential (total neutrophil count, lymphocyte, monocyte, eosinophil, and 
basophil counts), hemoglobin, hematocrit, and platelet count. 
• Blood chemistry:   Blood urea nitrogen (BUN), creatinine, sodium, potassium, calcium, 
chloride, bicarbonate (CO2), glucose, albumin, total protein, total bilirubin, alkaline 
phosphatase, AST (SGOT), ALT (SGPT).  
• LDH at screening (or C1D1 prior to first dose) then every day 1 of all cycles scheduled 
per protocol and end of treatment. 
• TSH to be obtained screening, every day 1 of cycles 2, 3, 4, and then every 3 cycles and 
end of treatment. If TSH is abnormal complete a T3/T4. 
• PSA to be obtained at screening, Day 1 of Cycle 1 and cycles 2, 3, 4, and every 3rd cycle 
going forward and at the end of treatment visit.  

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• Testosterone to be obtained at screening (or C1D1 prior to first dose) and C4D1. 
 
9.3 
ECG 
 
A standard 12-lead ECG is to be performed at screening and significant findings must be 
recorded.  Additional ECGs may be performed at the discretion of the treating physician.   
 
9.4 
Imaging 
 
A CT scan with contrast of chest, abdomen, and pelvis will be performed within 42 days prior to 
C1D1 visit, and every 3 cycles (approximately every 12 weeks) as part of routine tumor 
assessment.  These scans are to be performed on day 1 of every 3 cycles (i.e. screening, Day 1 
of cycles 4, 7, 10, etc.) within 7 days prior to starting the next cycle.  If the chest CT at screening 
is clear, chest x-rays may be used for subsequent assessments at the enrolling physician’s 
discretion. The tumor assessments will be performed locally, in strict accordance with the 
RECIST 1.1 guidelines (Note: during screening, metastatic disease may be confirmed by prostate 
cancer-specific PET imaging without meeting RECIST 1.1 criteria).  A total body bone scan will be 
performed within 42 days of C1D1 visit and every 3 cycles (approximately every 12 weeks) and 
interpreted according to modified PCWG3 guidelines. CT and bone scan modalities per standard 
institutional practices may be used, but the same modality should be used throughout the 
study for each subject. 
Because the primary endpoint is progression free survival based upon radiographic disease 
progression, patients will continue to have CT scans and Bone Scans performed according to 
standard clinical practice even if study treatment is discontinued for reasons other than 
radiographic disease progression.  
 
 
9.5 
Exploratory correlative studies 
 
9.5.1 
Ancestral Genotyping and SNP Analysis 
 
Human whole blood will be collected at baseline for DNA isolation.  Isolated DNA will be used 
for ancestral genotyping and characterization of SNPs.  To obtain genetically estimated 
indicators of race, ancestral genotyping will be performed. In addition, characterization of SNPs 
of the androgen receptor gene, androgen metabolism genes (including CYP19A1, HSD3B1, 
HSD17B4, SLCO2B1 and SLCO1B3), androgen signaling genes and 147 genes that we have 
shown to be differentially expressed in African American versus Caucasian prostate will be 
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plus apalutamide will be evaluated.  A genome wide association study (GWAS) is planned in 
both African American and Caucasian men with mCRPC and their associations with response to 
abiraterone acetate plus apalutamide. The local site will process these samples and prepare 
them for shipment to the lead site per shipping instructions below.  The lead site will perform 
the laboratory analysis.  Neither the local sites nor the patients will receive information 
regarding individual subjects’ results. 
 
9.5.2 
Hormone Levels and Metabolomics Profile Including Lipid Levels 
 
To assess hormone and lipid levels, serum will be collected at baseline, the end of cycle 3 (at 
Cycle 4 Day 1) and the end of treatment visit. A metabolomics profile will be conducted to 
assess lipids level. The metabolomics profile labs will be drawn fasting. The hormone analysis 
labs will be drawn fasting, when available. The hormone analysis labs may be performed with 
non-fasting samples when fasting is not available.  
 
Lipidomic analysis will be performed by Dr. Massimo Loda, Dr. Sara Bleve and Dr. David Nanus 
at Weill Cornell Medicine. As part of their analysis, samples may be sent to Lipometrix. This 
work will aim to identify a minimally invasive lipid biomarker of response to ARSI in Black and 
White men with mCRPC. Through liquid chromatography and mass spectrometry, we will detect 
lipidomic signatures associated with ARSI response in mCRPC and correlate the lipid alterations 
profiles with prostate racial disparity. 
9.5.2.1 
Steroid Hormone Analysis 
 
Steroid hormone analysis will occur at baseline, Cycle 4 Day 1 and end of treatment and be 
performed by Dr. Elahe Mostaghel and Dr. Bruce Montgomery as previously described. [36-38] 
This analysis will include up to 100 patients from this study and up to 100 patients from the Abi 
Race study (Pro00046383, NCT01940276). Abi Race enrolled 50 White patients receiving 
abiraterone acetate + prednisone and 50 Black patients receiving abiraterone acetate + 
prednisone.  
 
We will quantify steroid hormones, covering the full range of testicular and adrenal derived 
steroids (over 20 metabolites offered in 5 panels: androgens, estrogens, corticosteroids, 11-
hydroxy steroids, and sulfates) in serum specimens. The primary metabolites measured will 
include androstenedione (AED), testosterone, progesterone, pregnenolone, androsterone, 
dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and dehydroepiandrosterone 
sulfate (DHEAS). Using these data and clinical data from the Abi Race and PANTHER studies, we 
will assess race- and genetic ancestry-related steroid hormones and response to abiraterone 
and combination abiraterone and apalutamide in metastatic castration-resistant prostate 
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9.5.3 
Pharmacokinetics assessment 
  
For the pharmacokinetics assessment, we will analyze abiraterone acetate and metabolites 
produced by conversion of abiraterone acetate by steroid metabolizing enzymes. Specifically, 
we will analyze concentrations of Abi, D4A, 5α-Abi, 5β-Abi, 3-keto-5α-Abi, 3α-OH-5α-Abi, 3β-
OH-5α-Abi, 3-keto-5β-Abi, 3α-OH-5β-Abi and 3β-OH-5β-Abi. Concentrations of abiraterone 
acetate and the aforementioned metabolites will be analyzed in serum samples collected at 
two time points. Specifically, samples will be drawn on cycle 1 day 1 at 1, 2, 4, 8, hours post 
dose and cycle 2 day 1 at 24 hour trough, 1, 2, 4, and 8 hours post dose. Drug, drug metabolites 
and internal standard will be extracted from serum and analyzed using mass spectrometry as 
described by Li Z et al.84,85 There is a +/- 15 minute window for all PK lab draws, except for the 8 
hour timepoint. There is a +/- 1 hour window for the 8 hour timepoint.  Should a subject require 
a study drug hold during the two weeks prior to cycle 2 day 1, the PK draws will be delayed until 
the next cycle.  The subject should have taken two weeks of study drug prior to cycle 2 (or later) 
PK. Subject may miss two doses in the two weeks prior to PK draw, if not on drug hold. .  The 
Sponsor-Investigator must be notified of the delay.   
 
9.5.4 
Plasma samples for blood-based biomarkers 
 
Plasma samples will be assessed by multiplex ELISA for circulating cytokines and growth factors 
related to angiogenesis, immune response and inflammation.  Samples will be collected at 
baseline, at Cycle 2 Day 1, and end of treatment to define levels, patterns of expression and 
pharmacodynamics change during treatment. These additional biomarker analyses will be in 
support of the specified endpoints in the protocol. 
 
9.5.5 
Expression and Splicing Analysis 
 
RNA samples will be collected at baseline, cycle 4, and at progression or end of treatment to 
determine expression and splicing status of the androgen receptor gene, genes involved in 
androgen metabolism and signaling and genes that we have shown to be differentially 
expressed and/or spliced in African American versus Caucasian prostate cancer. Associations 
with response to abiraterone acetate plus apalutamide will be evaluated.  
 
 
9.5.6 
Cell-Free Plasma DNA Analysis 
 

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Cell-free plasma DNA profiles will be investigated at baseline and at progression or end of 
treatment. Associations with response to abiraterone acetate plus apalutamide will be 
evaluated.  
 
9.5.7 
Collection of Tumor Tissue for Somatic SNP, Expression and/or Splicing 
Assessments 
 
FFPE archival tumor tissue will be collected whenever available from all patients having 
undergone a diagnostic core biopsy or a surgery (prostatectomy or metastatic sampling).  Fresh 
frozen or FFPE samples will be batched and evaluated collectively by targeted sequencing, IHC, 
and/or QRT-PCR for the status of the androgen receptor gene, target genes involved in 
androgen metabolism and signaling, and target genes that have been shown to be differentially 
expressed and/or spliced in African American versus Caucasian prostate cancer.  Tumor content 
of samples will be confirmed using H&E. The relationship between germline and somatic DNA 
and RNA variants will be defined.   
 
In patients without target SNP alterations, it will be important to confirm that there are not 
somatic tumor alterations within these genes.  Discrepancies between germline and somatic 
mutations will be further evaluated.   Methodologies used and evaluations performed will be 
determined by the yield, tumor content and time points of specimens and DNA/RNA obtained. 
 
Samples will be stored by Dr. Jennifer Freedman, PhD with access limited to key personnel.  
DUHS will maintain these samples for up to 20 years. Upon completion of this protocol, these 
samples will be kept in long-term storage at the Duke BioRepository and Precision Pathology 
Center (BRPC) under the protocol designated IRB# Pro00035974. Any future analyses not 
specified in this protocol will be agreed upon by prior approval from Janssen Scientific Affairs, 
LLC.    
 
9.5.8 
Sample Collection, Storage and Shipping Instructions 
 
See Laboratory Manual for further details regarding sample collection, storage and shipping. 
 
Once complete, these samples will be analyzed for their appropriate endpoints, as indicated in 
the study (i.e. ancestral genotyping, SNPs, lipidomics, hormone levels, RNA transcripts, cell-free 
plasma DNAs and plasma biomarkers). Access to these samples will be limited to Drs. George, 
Freedman, Nixon, Sharifi, Mostaghel, Montgomery, Loda, Bleve, Nanus and their proxy staff 
and Lipometrix. These samples will be maintained for up to 20 years, and managed as described 
above.   Any future analyses not specified in this protocol will be agreed upon by prior approval 
from Janssen Scientific Affairs, LLC.   

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Ancestral genotyping will be done in collaboration with Rick Kittles, PhD,
 
SNP and RNA 
transcript analysis will be done in collaboration with the Duke Center for Genomic and 
Computational Biology Sequencing and Genomic Technologies Shared Resource, 
 
 determination of lipid and hormone levels will be done in 
collaboration with Biocrates Life Sciences AG, Eduard-Bodem-Gasse 8, 6020 Innsbruck, 
Austria,  and investigation of cell-free plasma DNA and plasma biomarkers will be done in 
collaboration with Andrew Nixon, PhD, 
 
 Pharmacokinetic and cell-free plasma 
DNA analysis will be done in collaboration with Dr Nima Sharifi, 
 
 
Steroid hormone analysis will be performed in collaboration with Dr. Elahe Mostaghel 
and Dr. Bruce Montgomery at the V.A.
 
Lipidomic analysis will be performed in 
collaboration with Dr. Massimo Loda, Dr. Sara Bleve and Dr. David Nanus at Weill Cornell 
Medicine, 
 Dr. Loda may send 
samples for lipidomic analysis to Lipometrix, 
  
9.6 
End of treatment 
 
The end of treatment visit will occur within 7 days (+/- 7days) of the last dose of study drug or 7 
days from the decision to remove the subject from the study if the subject has been off study 
drug more than 7 days.  
 
9.7 
Follow up safety visit 
The safety follow up visit will occur within 30 days (+/- 7 days) of the last dose of study drug.  
Adverse events must be followed for 30 days of the last dose of study drug. SAEs that remain 
open at the end of the follow up safety visit must be followed as detailed in section 11.5.1.  
 
9.8 
Follow-Up for Radiographic Progression 
 
During the Follow-up Period, subsequent therapy for prostate cancer should be assessed every 
3 months (+/- 14 days) for up to 24 months after the first dose of study drug.  Since the primary 
endpoint is progression free survival based upon radiographic disease progression, patients will 
continue to have CT scans and Bone Scans performed according to standard clinical practice 
until they have radiographic progression or until they have started another therapy for prostate 
cancer. 
 

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10.2 
Interruption or discontinuation of treatment 
 
All interruptions or changes to study drug administration must be recorded. 
 
It will be documented whether or not each patient completed the clinical study.  If for any 
patient either study treatment or observations were discontinued the reason will be recorded.   
 
Reasons that a patient may discontinue participation in a clinical study are considered to 
constitute one of the following: 
i. Disease progression by modified PCWG3 criteria 
ii. Clinical progression by the discretion of the treating physician 
iii. Need for radiation or new systemic therapy for prostate cancer 
iv. Unacceptable toxicity requiring cessation of therapy, including adverse 
event(s), abnormal laboratory value(s), or abnormal test/procedure result(s):  
Patients, who have sustained toxicities that do not return to NCI CTCAE 
(version 4.0) baseline grade with appropriate medical management, may be 
discontinued from the study treatment. 
v. Protocol violation 
vi. Patient withdrawal of consent - the reason(s) for withdrawal must be 
documented and clarification requested whether withdrawal of consent 
applies only to the Treatment Phase (i.e. patient has not withdrawn consent 
for data collection during the post-treatment Follow-Up Phase) or to both the 
Treatment and Follow-Up Phases. A patient’s decision to take part in the study 
is voluntary, and he may choose not to take part in the study or to stop taking 
part at any time. If he chooses not to take part or to stop at any time, it will not 
affect his future medical care. 
vii. Death 
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
must be followed at 4-week intervals or closer until resolution to Grade I or less.  For clinically 
significant laboratory changes resulting in treatment interruption or discontinuation, patients 
must have their values monitored at least once a week for 4 weeks, and subsequently at 4-
week intervals, until resolution to < Grade II or stabilization of the event, whichever comes first.  
If a patient requires an apalutamide dose delay of >21 days, or 28 days in cases of rash, from 
the day of the next scheduled dose, then the patient should discontinue treatment with 
apalutamide but remain on study for other study treatments (abiraterone acetate and 
prednisone as planned). Similarly, if a patient requires an abiraterone acetate dose delay of >21 
days, or 28 days in cases of rash, from the day of the next scheduled dose, then the patient 
should discontinue treatment with abiraterone acetate but remain on study for other study 
treatments (apalutamide as planned). All patients must be followed for adverse events and 
serious adverse events for 30 days following the last dose of apalutamide and/or abiraterone 
acetate.  All SAEs must be reported to Duke University as detailed in section 11.2-3. 

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An investigator may withdraw a patient from the study Treatment Phase at any time based on 
clinical judgment or for any of the following reasons listed above.  
 
11. 
SAFETY ASSESSMENTS AND REPORTING 
Safety assessments will consist of monitoring and recording all adverse and serious adverse 
events, the regular monitoring of hematology and blood chemistry values, regular 
measurement of vital signs, and the performance of physical examinations. 
 
These assessments should be performed within the windows as indicated on the schedule of 
events except for adverse events that will be evaluated continuously through the study.  Safety 
and tolerability will be assessed according to the NIH/NCI CTCAE v. 4.0. 
 
11.1 
Definitions 
 
 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. 
 
Adverse Events of Special Interest  
There are no adverse events of special interest identified for apalutamide or abiraterone 
acetate. 
 
Definition of Adverse Drug Reaction (ADR) 
 
A noxious and unintended response to any dose of the drug (or biological) product for which 
there is a reasonable possibility that the product cause the response.  ‘‘Reasonable possibility’’ 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event. Suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any adverse event caused by a drug. 
Individual Case Safety Report (ICSR) 

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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 
 
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/capsules 
• Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, 
needle detaching from syringe 
• Suspected Contamination 
• Suspected Counterfeit 
 
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 life-threatening 

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(The subject was at risk of death at the time of the event. It does not refer to an event 
that hypothetically might have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a suspected transmission of any infectious agent via a medicinal product 
• 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition 
above. These should usually be considered serious. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE EVENT. 
 
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.] 
 
Life-Threatening Conditions 
The cause of death of a subject in a study within 30-days of the last dose of apalutamide or 
abiraterone acetate drug, 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. 
 
11.2 
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 

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authorization, the expectedness of an adverse event will be determined by whether or not it is 
listed in the applicable product information.  
 
For Abiraterone acetate, the link to the package insert is: 
 
http://www.zytiga.com/sites/default/files/pdf/full product information.pdf 
 
For Apalutamide, the link to the package insert is: 
 
http://www.janssenlabels.com/package-insert/product-monograph/prescribing-
information/ERLEADA-pi.pdf 
 
11.3 
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) 
• 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  
• For Abiraterone acetate only, failure of expected pharmacological action (i.e., lack of 
effect) of 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 
• For Abiraterone acetate only, unexpected therapeutic or clinical benefit from use of 
a Janssen medicinal product 
 
These safety events may not meet the definition of an adverse event; however, from a 
JANSSEN 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 as described in 
section 11.8 REPORTING TIMELINES. 
 
11.3.1 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. 

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Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
11.4 
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 the request of JANSSEN Scientific Affairs, LLC. 
 
11.5 
Procedures for Reporting to JANSSEN SCIENTIFIC AFFAIRS 
Procedures for Reporting Adverse Events (AE), Serious Adverse Events (SAE), Special Reporting 
Situation, and Product Quality Complaints (PQCs) to JANSSEN SCIENTIFIC AFFAIRS 
 
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.  
 
All (serious and non-serious) adverse events reported for a Janssen medicinal product should be 
followed-up in accordance with clinical practice. 
Suspected theft, loss, or misplacement of any Janssen supplied study drug from either Duke or 
the subject’s supply should also be reported to Janssen.  
The sequence and timing of reporting requirements is described in section 11.8 Reporting 
Timelines.  
 
 
11.5.1 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 
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• 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  JANSSEN in English 
as described in section 11.8 REPORTING TIMELINES. 
In the event the study is blinded, the PRINCIPAL INVESTIGATOR will submit an unblinded SAE or 
pregnancy exposure report to JANSSEN. 
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, as described in section 11.8 REPORTING TIMELINES. 
All available clinical information relevant to the evaluation of a related SAE or special situation 
is required. 
• The INSTITUTION and/or PRINCIPAL INVESTIGATOR is 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 JANSSEN as 
described in section 11.8 REPORTING TIMELINES. 
 
11.5.2 Non-Serious AEs 
All non-serious adverse events should be reported to JANSSEN according to the timeframe 
outlined in the Research Funding Agreement section entitled Reporting of Data. 
11.5.3 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 JANSSEN, and are mandated by regulatory agencies worldwide. 
JANSSEN 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 JANSSEN 
by the PRINCIPAL INVESTIGATOR as described in section 11.8 REPORTING TIMELINES. The 
Janssen contact will provide additional information/form to be completed. 
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 

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PQC to JANSSEN according to the serious adverse event reporting timelines.  A sample of the 
suspected product should be maintained for further investigation if requested by JANSSEN. 
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. 
Transmission Methods 
The following methods are acceptable for transmission of safety information to JANSSEN 
SCIENTIFIC AFFAIRS: 
• Electronically via Janssen SECURE Email service (preferred) to secure email box:  
 
• For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report to 
 
• Telephone, if fax is non-functional: 
 
 
Please use the contact information and process information provided by JANSSEN SCIENTIFIC 
AFFAIRS.  
 
 
11.6 
Management of Adverse Events, Serious Adverse Events and Special Reporting 
Situations 
In general, the PI or designate must immediately report to JANSSEN SCIENTIFIC AFFAIRS any 
serious adverse event and Special Reporting Situations, whether or not considered drug 
related. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the drug and the event (e.g., death as a result of anaphylactic reaction or 
fatal hepatic necrosis). In that case, the investigator must immediately report the event to 
JANSSEN. The PI must record non-serious adverse events and report them to JANSSEN following 
completion of the accrual and follow up period or to fulfill regulatory reporting requirements. 
 
A Serious Adverse event or Special Reporting Situations must be reported if it occurs during a 
subject’s participation in the Study (whether receiving Study Product or not) starting with the 
date of signed consent and continuing until  30 days after receiving the last dose of Study 
Product. 
 
An Adverse Event or Product Quality Complaint must be reported starting with the first dose of 
Study Product and continuing until 30 days after receiving the last dose of Study Product. 
Any theft, loss, or misplacement of any Janssen supplied study drug from either Duke or the 
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until the end of the study. This applies even if there is no suspicion of misuse or overdose on 
the part of the subject.  
 
 
11.7 
Recording of Adverse Events, Serious Adverse Events and Special Reporting Situations 
 
Recording should be done in a concise manner using standard, acceptable medical terms. 
 
The adverse event recorded should not be a procedure or a clinical measurement (i.e. a 
laboratory value or vital sign) but should reflect the reason for the procedure or the diagnosis 
based on the abnormal measurement. 
 
Preexisting conditions that worsen in severity or frequency during the Study should also be 
recorded (a preexisting condition that does not worsen is not an adverse event). 
 
Further, a procedure or surgery is not an adverse event; rather, the event leading to the 
procedure or surgery is considered an adverse event. Any event requiring in-patient 
hospitalization that occurs during the course of a subject’s participation in a trial must be 
reported as an SAE. Hospitalizations that do not meet the criteria for SAE reporting are: 
A: 
Reasons described in the Protocol, e.g. drug administration, Protocol-required testing 
B. 
Surgery or procedure planned prior to entry into the Study. 
 
If, in the PRINCIPAL INVESTIGATOR’s judgment, a clinical significant worsening from baseline is 
observed in any laboratory or other test parameter (e.g. electrocardiogram (ECG), angiogram), 
physical exam finding, or vital sign, a corresponding clinical adverse event should be recorded. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should be recorded 
as the adverse event, whenever possible.  However, a complete description of the signs, 
symptoms and investigations which led to the diagnosis should be provided. For example, if 
clinically significant elevations of liver function tests are known to be secondary to hepatitis, 
“hepatitis” and not “elevated liver function tests” should be recorded. If the cause is not 
known, the abnormal test or finding should be recorded as an adverse event, using appropriate 
medical terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation). 
 
 
11.8 
Reporting Timelines 
 
Serious safety information (SAEs,  Special Reporting Situations, and PQCs), whether or not 
considered drug related, should be sent via the REDCap survey system using the web link 
provided by the Duke multisite coordinators. For more information on and access to the 
REDCap system, please contact the GU multisite team:  
  
 

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If Duke staff cannot be reached within 24 hours, the Sponsor-Investigator should be contacted: 
Dr. Daniel George 
  
 
 
The initial report for each SAE or death should include at minimum the following information: 
• 
protocol # and title 
• 
patient initials, study identification number, sex, age 
• 
date the event occurred 
• 
description of the SAE 
• 
dose level and cycle number at the time the SAE occurred 
• 
description of the patient’s condition 
• 
indication whether the patient remains on study 
• 
causality/attribution 
 
Signature by physician, PI or sub-PI 
 
Follow-up information including severity, action taken, concomitant medications, and outcome 
should be communicated to Duke as soon as possible. 
 
Upon receipt of the Serious Adverse Event Reporting form by Duke, the PI will be notified and 
be required to complete the PI assessment of the DCI Safety SAE Report Review Form.  Within 
24 hours of notification from the site, Duke staff will, in turn, send the Janssen SAE Report Form 
to Janssen. Safety information will be sent to Janssen by encrypted email using Cisco Registered 
Envelope Service to 
 Delivery and read receipt of the secure 
email will serve as evidence of successful communication.  
 
All non-serious AEs should be reported according to the timeframe outlined in the Research 
Funding Agreement section entitled Reporting of Data. 
 
11.9 
FDA Reporting Requirements 
 
The Sponsor-Investigator (Duke) is responsible for reporting serious adverse events to the FDA 
in accordance with applicable IND Safety Requirements (21 CFR 312.32).  
 
 
 
11.10 Dissemination of Safety Information from JANSSEN SCIENTIFIC AFFAIRS to 
INSTITUTION/PRINCIPAL INVESTIGATORS 
 
JANSSEN  will provide to the  INSTITUTION/PRINCIPAL INVESTIGATOR IND safety reports/SUSAR 
(Serious Unexpected Suspect Adverse Reaction) reports generated by the JANSSEN  for the 

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Study Product as they become available until all subjects in the Protocol have completed their 
last Study visit according to the Protocol  (i.e. Last Subject Last Visit has occurred). 
 
12. 
EFFICACY ASSESSMENTS 
 
12.1 
Baseline tumor evaluation 
 
Response and progression will be evaluated in this study using a combination of the 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [39]and the modified guidelines for prostate cancer endpoints developed by the 
Prostate Cancer Clinical Trials Working Group (PCWG3) [35]. 
 
Traditional measures of response reflect when a treatment is working and measures of 
progression indicate when a drug should be stopped.  Because assessing response in bone (the 
most common site of prostate cancer spread) is uncertain and the clinical significance of PSA 
changes in response to therapy is not a reliable predictor of response, measures of response 
have been expanded in consortium trials to include measures of progression. 
Patients will be reevaluated for response every cycle according to the guidelines below: 
 
Measurable disease:   According to RECIST 1.1, measurable disease is defined as at least 1 
lesion ≥ 10 mm in its longest diameter as measured by CT scan with slice thickness ≤ 5 mm, ≥ 10 
mm by clinical exam with caliper measurement, or ≥20 mm by CXR.  A lymph node is 
measurable if it is ≥ 15 mm in the short axis when assessed by CT scan.   All tumor 
measurements will be taken using a ruler or calipers and recorded in millimeters. 
 
Nonmeasurable disease:  Following RECIST 1.1, all other lesions (or sites of disease) will be 
considered nonmeasurable disease.  This includes small lesions (longest diameter < 10 mm) and 
any of the following: 
1. Leptomeningeal disease 
2. Ascites 
3. Pleural or pericardial effusion 
4. Lymphagitic involvement of the skin or lung 
5. Abdominal mass or organomegaly identified by physical exam but not by imaging 
techniques 
6. Bone lesions 
7. Lesions occurring within a previously irradiated area unless they are documented as 
new lesions since the completion of radiation therapy 
 
Target (nodal and visceral) lesions:  Following RECIST 1.1, progression in a nodal or visceral site 
(i.e., liver and lung) is sufficient to document disease progression.  The presence or absence of 
nodal and visceral disease before and after treatment should be recorded separately.  All 
measurable lesions (up to a maximum of 2 lesions per organ and 5 lesions in total) will be 

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identified as target lesions to be measured and recorded at baseline.  The target lesions should 
be representative of all involved organs.  Target lesions will be selected on the basis of size (i.e., 
the largest area) and suitability for accurate, repeated measurements.  Lymph nodes can be 
considered a target lesion if the short axis is ≥ 15 mm by CT.  The sum of diameters (long-axis 
for non-nodal lesions and short-axis for nodal lesions) of all target lesions will be calculated and 
reported as the baseline sum diameter.  The baseline sum diameter will be used as a reference 
by which to characterize the objective tumor response.   
 
Non-target lesions:  All other lesions (or sites of disease) will be identified as nontarget lesions 
and recorded at baseline.  Nontarget lesions will include measurable lesions that exceed the 
maximum number per organ (2) or total of all involved organs (5), as well as nonmeasurable 
lesions.  The presence or absence of these lesions will be recorded on the CRF and should be 
evaluated at the same assessment time points as all target lesions. 
 
PSA:   Because the rate of rise has known prognostic significance, estimate a pretreatment PSA 
doubling time (PSA-DT) if at least 3 values are available, but do not delay either treatment or 
enrollment onto a trial simply to estimate PSA-DT.   
 
12.2 
Response Criteria  
 
12.2.1 Evaluation of target lesions: 
 
Table 5 RECIST 1.1 response criteria for target (soft tissue)lesions 
Response 
Evaluation of Target Lesions 
Complete response (CR) 
The disappearance of all target lesions.  Any pathologic 
lymph nodes (target or non-target) must have reduction 
in short axis to <10 mm.   
Partial response (PR) 
A ≥30% decrease in the sum diameter of target lesions as 
compared to the baseline sum diameter. 
Progressive disease (PD)  
A ≥20% increase in the sum diameter of target lesions as 
compared to the smallest sum diameter on study.  This 
must show an absolute increase of at least 5 mm.  
The appearance of one or more new lesions.   
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD based on the smallest 
sum diameter on study.  
 
Target lesions that are too small to measure will be given a measurement of either 0 mm, if the 
radiologist believes the lesion has disappeared, or 5 mm, if the lesion is felt to be present.  In 
some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
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will be investigated with a fine needle aspirate or biopsy before confirming the complete 
response status.   
If lymph nodes have been identified as target lesions, the short axis measurement will be 
recorded even if the nodes regress to < 10 mm.  Therefore, the sum diameter may not be zero 
even if complete response criteria are met.       
 
12.2.2 Evaluation of non-target lesions: 
 
Table 6   RECIST 1.1 response criteria for non-target lesions 
Response 
Evaluation of Non-target Lesions 
Complete response (CR) 
The disappearance of all non-target lesions.  All lymph 
nodes must be <10 mm by short axis.  
Non-CR, Non-PD 
The persistence of one or more non-target lesions. 
Progressive disease (PD) 
Unequivocal progression of existing non-target lesions 
and/or the appearance of one or more new lesions. 
 
A clear progression of nontarget lesions only is exceptional.  In such circumstances, the 
progression status, as assigned by the investigator, may be reviewed by a PCCTC panel. 
 
New lesions:  If unequivocal, the appearance of new lesions denotes disease progression.  If a 
new lesion is equivocal, therapy will be continued and this lesion will be reevaluated on follow-
up imaging as planned in the study flow chart.  If repeat scans confirm the new lesion, 
progression will be documented using the date of the initial equivocal scan.  New brain 
metastases identified while on study are considered new even if there was no baseline brain 
imaging. 
12.2.3 Bone lesions 
 
Record post-treatment changes as either “no new lesions” or “new lesions.”  When the bone 
scan is the sole indicator of progression, disease progression in bone is defined as 2 or more 
new lesions seen on bone scan compared with the baseline scan used for trial entry.  In 
situations where scan findings suggest a flare reaction or where new lesion(s) may represent 
trauma, confirm these results with other imaging modalities.  In the absence of clearly 
worsening soft-tissue (nodal and visceral) disease or disease-related symptoms, progression at 
the first scheduled assessment should be confirmed on a second scan performed 6 or more 
weeks later.  The first post treatment bone scan (the cycle 4 bone scan) will be used as the 
baseline bone scan with which all future bone scans are compared per PCWG3. 
 
12.2.4 PSA 
 

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To report PSA-based outcomes, PCWG3 recommends that the percent of change in PSA from 
Cycle 1 day 1 to 12 weeks (or earlier for those who discontinue therapy) and the maximum 
decline in PSA that occurs at any point after treatment be reported for each patient using a 
waterfall plot.  Because declines in serum PSA, if they occur, may not do so for several weeks, 
PSA measurements obtained during the first 12 weeks should not be used as the sole criterion 
for clinical decision making.  As long as patient safety is the primary concern, in the absence of 
other indicators of disease progression, therapy should not be discontinued solely on the basis 
of a rise in PSA.   
 
12.2.5 Symptoms 
 
Transient increases in pain may occur before improvement, and those occurring in the first 12 
weeks should not affect the course of treatment in the absence of other compelling evidence of 
disease progression.  Changes in symptoms should be documented and confirmed as per other 
outcome measures.   
 
12.2.6 Evaluating best overall response 
 
The best overall response is the best response recorded from the start of treatment until the 
end of treatment. The investigator’s determination of best overall response will be based both 
on response criteria and on confirmation criteria.  To be assigned a status of partial response or 
complete response, changes in tumor measurements must be confirmed by repeat assessment 
performed 6-8 weeks after the criteria for response are first met.  To confirm stable disease, 
follow-up measurements must meet SD criteria at a minimum interval of 6 weeks after SD was 
first documented.  Table 7 will be used as an assessment tool. 
 
Table7. Assessing Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; PD, progressive disease; PR, partial 
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Patients with global deterioration of health status who require treatment to be discontinued 
without objective evidence of disease progression should be classified as having symptomatic 
deterioration.  Every effort should be made to document their objective progression, even after 
discontinuing treatment. 
Patients who do not have tumor response assessment due to rapid progression or toxicity will 
be considered nonresponders, will be included in the denominator for the response rate, and 
will be classified into one of the categories listed below: 
• Death attributed to disease progression 
• Early discontinuation attributed to disease progression 
• Death attributed to drug toxicity 
• Early discontinuation attributed to drug toxicity 
 
Note:  If a patient receives subsequent therapy before tumor progression is documented, the 
reason for changing therapy must be reported.  Reasons include clinical progression, drug 
toxicity, or secondary therapy for maintaining tumor response. 
 
12.3 
Confirming time-to-event outcomes 
 
Any on treatment change in disease status, be it favorable or unfavorable (PR, CR, SD, or PD), 
should be confirmed using a second assessment at a later time point, either 6 weeks later or 
at the next scheduled scan. 
 
12.4 
Duration of overall response 
 
Duration of overall response is measured from the time when partial response or complete 
response is first noted until the date when recurrent or progressive disease is objectively 
documented.  Duration of overall complete response is measured from the time the criteria for 
complete response are first met until the first date that recurrent disease is objectively 
documented.  Duration of stable disease is measured from the start of treatment until the 
criteria for progression are met. 
 
12.5 
Radiographic Progression-free survival 
The primary endpoint is radiographic progression-free survival (rPFS), a composite endpoint 
using the time from study entry to disease progression.   
 
Progression is defined as Radiologic progression by RECIST 1.1 [39] and/or bone scan 
progression by modified PCWG3 criteria [35](Appendix 4). 
A rise in PSA alone in the absence of radiologic or symptomatic indicators of disease 
progression, will not be considered disease progression.   Increased pain alone, in the absence 
of changes in imaging or need for radiation therapy, will not be considered disease progression. 
 

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All assessments of disease should be collected at the same time interval.  Post-treatment 
changes will be confirmed based on measurable target lesions, radionuclide bone scans, and 
symptoms as indicated below.  Patients who withdraw from study treatment for reasons 
other than radiographic disease progression should continue to have results of their CT and 
Bone scans collected and recorded during the Follow-Up phase until demonstration of 
radiographic progression. 
 
12.6 
Secondary endpoint assessments 
 
12.6.1 RECIST 1.1 defined radiologic response rates   
 
Tumor assessments by CT chest/abdomen/pelvis and bone scan will be made at baseline and 
every 12 weeks while on therapy.   If the chest CT at baseline is clear, chest x-rays may be used 
for subsequent assessments at the enrolling physician’s discretion. Response rates will be 
calculated based on RECIST 1.1 criteria, as detailed in section 12.2 above centrally.   Response 
rates will be analyzed using objective (defined as CR or PR) parameters.  
 
 
 
12.6.2 Safety and toxicity monitoring  
 
National Cancer Institute Common Toxicity Criteria (v 4.0) will be used to record and monitor 
for adverse events (Appendix 4). Data for safety and severe adverse events will be monitored 
on an ongoing basis through monthly investigator and staff meetings, including data from all 
centers involved.  
 
Summary statistics will be provided for the adverse events found in the common group of 
adverse events (≥10%).  This will include: GI disorders; fatigue; decreased appetite; 
hypokalemia; Dysgeusia; hot flush; rash; falls; and hypertension.  Less common adverse events 
(≤10%) include; insomnia; increase in blood cholesterol and triglycerides; and alanine 
aminotransferase increased and aspartate aminotransferase increased.  Rare but serious 
adverse events (may occur in less than 1 subject in 100) would include seizures.  This will 
include: mineralocorticoid excess (hypertension, hypokalemia, fluid retention); hepatotoxicity; 
cardiac disorders; osteoporosis-related fractures; rhabdomyolysis/myopathy; drug-drug 
interaction (CYP2D6); allergic alveolitis and seizures.  Refer to section 11.1.  
 
 
TSH 

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Changes in TSH have been observed in the ongoing early phase and blinded Phase 3 studies. 
The changes in TSH from baseline have been observed both in subjects with and without a 
history of thyroid disorders, however, the largest numerical increases in TSH have been 
observed in subjects on thyroid hormone replacement. Increases in TSH are at times associated 
with decreases in T3 or T4 or both. The mechanism for this observed TSH change and the 
associated alterations in thyroid function are still under investigation. Thyroid function should 
be monitored and doses of replacement hormones should be started or adjusted based on 
laboratory findings. 
 
12.7 
Exploratory endpoints 
 
i. 
Hormone Levels and Metabolomics Profile including Lipid Levels 
We will describe the baseline profile of serum hormone levels (including but not limited to 
testosterone, DHT, DHEA, DHEAS, estradiol) and lipids, the change in levels with subsequent 
therapy (Cycle 4), and their correlation with response to abiraterone acetate plus apalutamide.  
 
Steroid Hormone Analysis 
We will use the Random Lasso approach to assess race- and genetic ancestry-related steroid 
hormones and response to abiraterone and combination abiraterone and apalutamide in 
metastatic castration-resistant prostate cancer (mCRPC).[40] In our preliminary work on Abi 
Race, we recognized that the modest sample size suggested the use of the Random Lasso. In 
our current collaborative work with this team, we have set up the code required to implement 
this approach, which utilizes a two-step approach across bootstrap samples. This method has 
been shown to select all relevant targets, even in the presence of high correlation, eliminating 
targets with a trivial role. Another advantage of the approach is that internal validation using 
bootstrap avoids the small sample sizes that would occur with cross-validation. We will 
implement this approach, incorporating global genetic ancestry (non-penalized), critical clinical 
covariates and steroid hormone levels. 
 
This analysis will include samples from both this study and Abi Race (Pro00046383, 
NCT01940276). We expect to analyze up to 200 samples: 50 White patients receiving 
abiraterone, 50 Black patients receiving abiraterone, 50 White patients receiving combination 
abiraterone and apalutamide, 50 Black patients receiving combination abiraterone and 
apalutamide. Using the steroid hormone analysis data and clinical data from the Abi Race and 
PANTHER studies, we will assess race- and genetic ancestry-related steroid hormones and 
response to abiraterone and combination abiraterone and apalutamide in metastatic 
castration-resistant prostate cancer (mCRPC). 
 

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ii. 
Abiraterone pharmacokinetics  
Abiraterone acetate is metabolized to an active metabolite (D4A), that may function as an 
androgen receptor antagonist. It is unknown whether this metabolism is linked to race, 
therefore we will explore abiraterone acetate and active metabolite drug levels in this study.  
(PKs) will be drawn on cycle 1d1 (at 1, 2, 4 and 8 hours post dose) and cycle 2d1 (at 24 hour 
trough, 1, 2, 4 and 8 hours post dose) of study drug.  
 
iii. 
Ancestral Genotyping and SNP Analyses   
We will perform ancestral genotyping to obtain genetically estimated indicators of race.  In 
addition, we will describe the germline SNP profiles of the androgen receptor gene, target 
genes involved in androgen metabolism and signaling and target genes that have been shown 
to be differentially expressed in African American versus Caucasian prostate cancer and their 
associations with response to abiraterone acetate plus apalutamide. The status of the 
aforementioned targets will also be assessed in archival tumor tissue, if available. 
iv. 
Expression and Splicing Analysis 
We will describe the expression and splicing profiles of the androgen receptor gene, target 
genes involved in androgen metabolism and signaling and target genes that have been shown 
to be differentially expressed and/or spliced in African American versus Caucasian prostate 
cancer and their associations with response to abiraterone acetate plus apalutamide. The 
status of the aforementioned targets will also be assessed in archival tumor tissue, if available. 
v. 
Cell-Free Plasma DNA Analysis 
We will describe cell-free plasma DNA profiles and their associations with response to 
abiraterone acetate plus apalutamide. 
vi. 
Plasma-Based Biomarker Analysis  
We will describe the profile of plasma blood-based biomarkers that may have prognostic or 
predictive value and their associations with response to abiraterone acetate plus apalutamide. 
  
13. 
STATISTICAL METHODS 
The primary endpoint is radiographic progression-free survival (rPFS), as assessed by the 
investigator, which is defined as the duration from the date of study enrollment to the date of 
first documentation of radiographic progressive disease or death due to any cause, whichever 
occurs first. Secondary endpoints are overall survival (OS), 12 month PSA PFS and other PSA 
changes, radiographic assessments and safety. OS is defined from the date of study enrollment 
to date of death due to any cause. Biochemical progression is defined from date of study 
enrollment to date of PSA progression as defined by the modified PCWG3. 
 
 
 
Sample Size Justification  

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This trial is non-comparative. Based on Ryan et al. the median time to radiographic progression 
free survival (rPFS) is 16.5  months [41]. Fifty (50) patients will be enrolled in each group (AA 
and Caucasians). With an accrual rate of 50 patients/group over 20-month accrual period, 24-
months follow-up, and assuming that rPFS follows an exponential distribution, based on 5000 
simulations the average width of a two-sided 95% confidence interval for the median rPFS is 16. 
Because of the small sample size and short follow-up period, 26 radiographic PFS events/group 
are expected. Consequently, the radiographic PFS distribution by racial group will not be 
estimated with high precision.  
Data Analysis 
An intent-to-treat approach will be used for the analyses within each racial group of all clinical 
outcomes except safety where patients who have received at least one dose of study treatment 
will be included in the analysis. The proportion of patients who experience PSA decline of 30%, 
50% and 90% within 3 months on study will be estimated with 95% confidence intervals based 
on the binomial distribution. In addition, post therapy changes in PSA will be explored as a 
continuous variable. The Kaplan-Meier product limit method will be used to estimate the rPFS, 
biochemical PFS and OS distributions. 
 
Serum hormone, serum lipid, SNP, gene expression, alternative splicing, cell-free plasma DNA 
and plasma-based biomarker profiles will be summarized using descriptive statistics. 
 
The GWAS analysis will be mostly exploratory as the trial limited sample size will not permit 
definitive analyses.  Call rate, patterns of missing data, and departures from the Hardy-
Weinberg equilibrium will be performed using exact test to identify SNPs that will not be used 
in analysis.   Allele frequencies estimated within each racial group separately. Although race is 
self-reported, admixture estimates and will be adjusted for in the analysis. Test for association 
will be performed under an additive model. 
 
 
14. 
DATA REPORTING AND REGULATORY REQUIREMENTS  
 
14.1 
Data Entry 
 
Data collected during this study will be entered into a secure Medidata Rave database.  Staff at 
Duke University will be responsible for the initial study configuration and setup in the electronic 
database as well as for any future changes.   
 
 
14.1.1 Case report forms 
 

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Electronic case report forms (CRFs) will be generated by Duke University for the collection of all 
study data.  Site Investigators or designee will be responsible for ensuring that the CRFs are 
kept up-to-date. Each site will enter their own data into CRFs from source documents on site.   
14.1.2 Source documents 
 
Study documentation includes all paper case report forms, data correction forms, source 
documents, monitoring logs and appointment schedules, sponsor-investigator correspondence 
and regulatory documents (e.g., signed protocol and amendments, Ethics or Institutional 
Review Committee correspondence and approval, approved and signed subject consent forms, 
Statement of Investigator form, and clinical supplies receipts and distribution records). 
 
The investigator will prepare and maintain complete and accurate study documentation in 
compliance with Good Clinical Practice standards and applicable federal, state, and local laws, 
rules and regulations; and, for each subject participating in the study, promptly complete all 
original case report forms and such other reports as required by this protocol following 
completion or termination of the clinical study or as otherwise required pursuant to any 
agreement with the Sponsor-Investigator. 
By signing the protocol, the investigator acknowledges that, within legal and regulatory 
restrictions and institutional and ethical considerations, study documentation will be promptly 
and fully disclosed to the Sponsor-Investigator/Regulatory Specialist by the investigator upon 
request and also shall be made available at the investigator’s site upon request for inspection, 
copying, review and audit at reasonable times by representatives of Sponsor-Investigator or 
responsible government agencies as required by law.  The investigator agrees to promptly take 
any reasonable steps that are requested by Sponsor-Investigator as a result of an audit to cure 
deficiencies in the study documentation and case report forms. 
 
14.1.3 Record retention 
 
The investigator will maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified.  After study 
closure, each participating site’s PI will maintain all source documents, study-related 
documents, and CRFs.  Because the length of time required for retaining records depends upon 
a number of regulatory and legal factors, documents should be stored until the investigator is 
notified that the documents may be destroyed.  In this study, records are to be retained and 
securely stored for a minimum of 6 years after the completion of all study activities. 
 
14.2 
Study monitoring and quality assurance 
 
The Sponsor-Investigator is responsible for monitoring the protocol to ensure that the 
investigation is conducted in accordance with the general investigational plan and all applicable 

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regulatory requirements.  In addition, the protocol will be monitored independently via the 
Duke Cancer Center (DCI) Monitoring Team. 
 
The DCI Monitoring Team will conduct monitoring visits to ensure subject safety and to ensure 
that the protocol is conducted, recorded, and reported in accordance with the protocol, 
standard operating procedures, good clinical practice, and applicable regulatory 
requirements.  As specified in the DCI Data and Safety Monitoring Plan, the DCI Monitoring 
Team will conduct routine monitoring after the third subject is enrolled, followed by twice- 
annual monitoring of 1 – 3 subjects until the study is closed to enrollment and subjects are no 
longer receiving study interventions that are more than minimal risk.   
 
The DCI Safety Oversight Committee (SOC) will perform  reviews on findings from the DCI 
Monitoring Team visit and additional safety and toxicity data submitted by the Principal 
Investigator. 
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected 
frequency of serious and/or unexpected toxicities, or other concerns and may be initiated upon 
request of DUHS and DCI leadership, the CPC, the Safety Oversight Committee (SOC), the Duke 
OARC, the sponsor, the Principal Investigator, or the IRB.  All study documents must be made 
available upon request to the DCI Monitoring Team and other authorized regulatory 
authorities, which may include but is not limited to the National Institute of Health, National 
Cancer Institute, and the FDA.  Every reasonable effort will be made to maintain confidentiality 
during study monitoring. 
 
14.3 
Data Safety and Monitoring  
 
Data for safety and severe adverse events will be monitored on an ongoing basis through 
monthly investigator and staff meetings, including data from all centers involved.   
 
In addition a recruitment and withdrawal summary will be discussed at these meetings.  
Withdrawals will be broken down into those due to AEs and what they were.    
  
In terms of internal review, the Investigator will continuously monitor and tabulate adverse 
events.  Appropriate reporting to the DUHS IRB will be made.  If an unexpected frequency of 
Grade III or IV events occurs, depending on their nature, action appropriate to the nature and 
frequency of these adverse events will be taken.  This may require a protocol amendment, dose 
de-escalation, or closure of the study.  The Investigator of this protocol will also continuously 
monitor the conduct, data, and safety of this protocol to ensure that: 
• Risk/benefit ratio is not altered to the detriment of the subjects 
• Appropriate internal monitoring of adverse events and outcomes is done 

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• Over-accrual does not occur 
• Under-accrual is addressed with appropriate amendments or actions 
• Data is being appropriately collected in a reasonably timely manner 
 
This protocol is being conducted at additional sites external to Duke University Health Systems.  
The Sponsor-Investigator is responsible for monitoring these sites to assure the safety and 
protection of all subjects, and to assure that the study is conducted, recorded, and reported in 
accordance with the protocol and applicable regulations.  To assure that the investigator 
obligations are fulfilled and all applicable regulations and guidelines are being followed, the 
Sponsor-Investigator will designate the DCI Monitoring Team to assure that the external site 
facilities are acceptable, the protocol and investigational plan are being followed, the IRB/IEC has 
been notified of approved protocol changes as required, complete records are being maintained, 
appropriate and timely reports have been made to the Sponsor-Investigator and the IRB/IEC, study 
drug and study drug inventory are controlled and the Investigator is carrying out all agreed 
activities.  Monitoring also includes review of regulatory and eligibility, conduct, data quality and 
adverse event reporting for select cases.  
 
As pre-arranged by the Sponsor-Investigator, DCI Monitoring Team will monitor 1-3 subjects 
twice annually at external sites until closed to enrollment or subjects are no longer receiving 
study drug or other interventions that are more than minimal risk.  Study teams will provide 
requested data for remote monitoring when possible.  If feasible, the first visit will be 
conducted on site.  Additional on-site visits will be completed as deemed necessary and as 
requested.  Additional review will be performed on a site-by-site basis, as warranted by the 
findings of previous monitoring visits.  Key variables (demographics, inclusion/exclusion criteria, 
and safety) on the CRFs will be compared with select subject’s source documents.  Any 
discrepancies will be noted and resolved. 
 
15. 
PROTOCOL AMENDMENTS OR CHANGES IN STUDY CONDUCT 
 
Any change or addition to this protocol requires a written protocol amendment that must be 
reviewed by Duke University and Janssen Scientific Affairs before implementation.   
 
16. 
PROCEDURES AND INSTRUCTIONS 
 
16.1 
Disclosure and confidentiality 
 
The investigator agrees to keep all information provided by participating sites and by Janssen 
Scientific Affairs in strict confidence and to request similar confidentiality from his/her staff and 
the IRB/IEC/REB.  Study documents provided by participating sites and Janssen Scientific Affairs 
(investigators' brochures and other material) will be stored appropriately to ensure their 

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confidentiality. The information provided by participating sites and Janssen Scientific Affairs to 
the investigator may not be disclosed to others without direct written authorization from 
Janssen Scientific Affairs, except to the extent necessary to obtain informed consent from 
patients who wish to participate in the trial. 
 
16.2 
Discontinuation of study 
 
Duke University or Janssen Scientific Affairs reserves the right to discontinue any study under 
the conditions specified in the clinical trial agreement. 
 
16.3 
Ethics and Good Clinical Practice 
 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in ICH Harmonized Tripartite Guidelines for Good Clinical Practice 
1996. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community.  US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations).  The investigator agrees to adhere to 
the instructions and procedures described in it and thereby to adhere to the principles of Good 
Clinical Practice that it conforms to. 
 
16.3.1 Institutional Review Board/Independent Ethics Committee 
 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB).  A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Janssen before study initiation.  Any amendments to the 
protocol, other than administrative ones, must be reviewed by Janssen Scientific Affairs, and 
approved by this committee. 
 
16.3.2 Informed consent 
 
The investigator or designee must explain to each subject (or legally authorized representative) 
the nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits involved and any discomfort it may entail.  Each subject must be 
informed that participation in the study is voluntary and that he may withdraw from the study 
at any time and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician. 
 

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This informed consent should be given by means of a standard written statement, written in 
non-technical language.  The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document.  If the subject cannot read or 
sign the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents.  No patient can enter the study before 
his/her informed consent has been obtained.  The informed consent form is considered to be 
part of the protocol, and must be submitted by the investigator with it for IRB/IEC/REB 
approval. 
16.3.3 Declaration of Helsinki 
 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki and amendments, concerning medical research in humans (Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects). Copies of the Declaration of 
Helsinki and amendments will be provided upon request or can be accessed via the website of 
the World Medical Association at http://www.wma.net/e/policy/17-c e.html. 

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REFERENCES 
 
 
1. 
Eisenberger, M.A., et al., Bilateral orchiectomy with or without flutamide for metastatic 
prostate cancer. N Engl J Med, 1998. 339(15): p. 1036-42. 
2. 
Crawford, E.D., et al., A controlled trial of leuprolide with and without flutamide in 
prostatic carcinoma. N Engl J Med, 1989. 321(7): p. 419-24. 
3. 
Schmitt, B., et al., Combined androgen blockade with nonsteroidal antiandrogens for 
advanced prostate cancer: a systematic review. Urology, 2001. 57(4): p. 727-32. 
4. 
Forti, G., et al., Three-month treatment with a long-acting gonadotropin-releasing 
hormone agonist of patients with benign prostatic hyperplasia: effects on tissue 
androgen concentration, 5 alpha-reductase activity and androgen receptor content. J 
Clin Endocrinol Metab, 1989. 68(2): p. 461-8. 
5. 
Mohler, J.L., et al., The androgen axis in recurrent prostate cancer. Clin Cancer Res, 
2004. 10(2): p. 440-8. 
6. 
Chen, C.D., et al., Molecular determinants of resistance to antiandrogen therapy. Nat 
Med, 2004. 10(1): p. 33-9. 
7. 
Stigliano, A., et al., Increased metastatic lymph node 64 and CYP17 expression are 
associated with high stage prostate cancer. J Endocrinol, 2007. 194(1): p. 55-61. 
8. 
Montgomery, R.B., et al., Maintenance of intratumoral androgens in metastatic prostate 
cancer: a mechanism for castration-resistant tumor growth. Cancer Res, 2008. 68(11): p. 
4447-54. 
9. 
Logothetis CJ, W.S., Molina A, Chieffo N, Smith P, Troncoso E, et al. Identification of an 
androgen withdrawal responsive phenotype in castrate resistant prostate cancer (CRPC) 
patients (pts) treated with abiraterone acetate (AA). ASCO 2008; 26:Abstract 5017. 
10. 
Taplin, M.-E., et al., Androgen receptor mutations in androgen-independent prostate 
cancer: Cancer and Leukemia Group B Study 9663. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology, 2003. 21(14): p. 2673-8. 
11. 
Tomlins, S.A., et al., Recurrent fusion of TMPRSS2 and ETS transcription factor genes in 
prostate cancer. Science, 2005. 310(5748): p. 644-8. 
12. 
Setlur, S.R., et al., Estrogen-dependent signaling in a molecularly distinct subclass of 
aggressive prostate cancer. J Natl Cancer Inst, 2008. 100(11): p. 815-25. 
13. 
Helgeson, B.E., et al., Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions 
in prostate cancer. Cancer Res, 2008. 68(1): p. 73-80. 
14. 
Perner, S., et al., TMPRSS2:ERG fusion-associated deletions provide insight into the 
heterogeneity of prostate cancer. Cancer research, 2006. 66(17): p. 8337-41. 
15. 
Demichelis, F., et al., TMPRSS2:ERG gene fusion associated with lethal prostate cancer in 
a watchful waiting cohort. Oncogene, 2007. 26(31): p. 4596-9. 
16. 
Mehra, R., et al., Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate 
adenocarcinoma: molecular evidence for an independent group of diseases. Cancer Res, 
2007. 67(17): p. 7991-5. 
17. 
Attard, G., et al., Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal 
human prostate cancer. Oncogene, 2008. 27(3): p. 253-63. 

PANTHER 
 
Page 75 of 83 
DukeUniversity 
 
CONFIDENTIAL 
 
18. 
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, 2008. 26(28): p. 4563-71. 
19. 
Attard G, R.A., Barrett M, Karavasilis V, Molife R, Thompson E, et al. Inhibition of 
androgen synthesis results in a high response rate in castration refractory prostate 
cancer. In: American Association for Cancer Research Annual Meeting: Proceedings; 
2007 Apr 14-18; Los Angeles, CA. Philadelphia (PA): AACR; 2007, Abstract LB-180. 
20. 
Barrie, S.E., et al., Pharmacology of novel steroidal inhibitors of cytochrome P450(17) 
alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol, 1994. 50(5-6): p. 
267-73. 
21. 
O'Donnell, A., et al., Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase 
inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer, 
2004. 90(12): p. 2317-25. 
22. 
de Bono, J.S., et al., Prednisone plus cabazitaxel or mitoxantrone for metastatic 
castration-resistant prostate cancer progressing after docetaxel treatment: a 
randomised open-label trial. Lancet, 2010. 376(9747): p. 1147-54. 
23. 
Ryan, C.J., et al., Interim analysis (IA) results of COU-AA-302, a randomized, phase III 
study of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with metastatic 
castration-resistant prostate cancer (mCRPC). J Clin Oncol, 2012. 30(Suppl). 
24. 
Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics, 2012. CA Cancer J Clin, 2012. 
62(1): p. 10-29. 
25. 
Litman, H.J., et al., Serum androgen levels in black, Hispanic, and white men. J Clin 
Endocrinol Metab, 2006. 91(11): p. 4326-34. 
26. 
Carson, A.P., et al., Trends and racial differences in the use of androgen deprivation 
therapy for metastatic prostate cancer. J Pain Symptom Manage, 2010. 39(5): p. 872-81. 
27. 
Holmes, L., Jr., et al., Impact of androgen deprivation therapy on racial/ethnic disparities 
in the survival of older men treated for locoregional prostate cancer. Cancer Control, 
2009. 16(2): p. 176-85. 
28. 
Giovannucci, E., et al., The CAG repeat within the androgen receptor gene and its 
relationship to prostate cancer. Proc Natl Acad Sci U S A, 1997. 94(7): p. 3320-3. 
29. 
Ross, R.W., et al., Inherited variation in the androgen pathway is associated with the 
efficacy of androgen-deprivation therapy in men with prostate cancer. J Clin Oncol, 
2008. 26(6): p. 842-7. 
30. 
Yang, M., et al., SLCO2B1 and SLCO1B3 may determine time to progression for patients 
receiving androgen deprivation therapy for prostate cancer. J Clin Oncol, 2011. 29(18): p. 
2565-73. 
31. 
Powell, I.J., et al., Genes associated with prostate cancer are differentially expressed in 
African American and European American men. Cancer Epidemiol Biomarkers Prev, 
2013. 
32. 
Reichardt, J.K., et al., Genetic variability of the human SRD5A2 gene: implications for 
prostate cancer risk. Cancer Res, 1995. 55(18): p. 3973-5. 
33. 
Wallace, T.A., et al., Tumor immunobiological differences in prostate cancer between 
African-American and European-American men. Cancer Res, 2008. 68(3): p. 927-36. 

PANTHER 
 
Page 76 of 83 
DukeUniversity 
 
CONFIDENTIAL 
 
34. 
Wang, B.D., et al., Androgen receptor-target genes in african american prostate cancer 
disparities. Prostate Cancer, 2013. 2013: p. 763569. 
35. 
Scher, H.I., et al., Design and end points of clinical trials for patients with progressive 
prostate cancer and castrate levels of testosterone: recommendations of the Prostate 
Cancer Clinical Trials Working Group. J Clin Oncol, 2008. 26(7): p. 1148-59. 
36. 
Mostaghel, E.A., et al., Circulating and Intratumoral Adrenal Androgens Correlate with 
Response to Abiraterone in Men with Castration-Resistant Prostate Cancer. Clin Cancer 
Res, 2021. 27(21): p. 6001-6011. 
37. 
Mostaghel, E.A., et al., Association of Tissue Abiraterone Levels and SLCO Genotype with 
Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized 
Prostate Cancer. Clin Cancer Res, 2017. 23(16): p. 4592-4601. 
38. 
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, 2014. 32(33): p. 3705-15. 
39. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
40. 
Wang, S., et al., Random Lasso. Ann Appl Stat, 2011. 5(1): p. 468-485. 
41. 
Ryan, C.J., et al., Abiraterone in Metastatic Prostate Cancer without Previous 
Chemotherapy. New England Journal of Medicine, 2013. 368(2): p. 138-148. 

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APPENDIX 1:  PERFORMANCE STATUS CRITERIA 
Karnofsky Performance Scale 
% 
Description 
100 
Normal, no complaints, no 
evidence of disease 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease 
80 
Normal activity with effort, 
some signs or symptoms of 
disease 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work 
60 
Requires occasional assistance 
but is able to care for most 
needs 
50 
Requires considerable 
assistance and frequent 
medical care 
40 
Disabled, requires special care 
and assistance 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
20 
Very sick, hospitalization 
indicated. Death not 
imminent. 
10 
Moribund, fatal processes 
progressing rapidly 
0 
Dead 
 
 

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APPENDIX 2:  CYP450 ISOENZYME INHIBITORS AND INDUCERS TO BE USED WITH CAUTION 
Strong CYP3A4,5,7 inhibitors 
Moderate CYP3A 4,5,7 inhibitors 
CYP3A4 inducers 
Clarithromycin 
Amprenavir 
 Avasimibe 
Conivaptan 
Aprepitant 
 Bosentan 
grapefruit juice 
Atazanavir 
Carbamazepine 
Indinavir 
Cimetidine 
Efavirenz  
Itraconazole 
Darunavir 
Modafinil 
 
Diltiazem 
Nafcillin  
Lopinavir 
Elvitegravir 
Oxcarbazepine 
Mibefradil 
Erythromycin 
Phenobarbital 
Nefazodone 
Fluconazole 
Phenytoin 
Nelfinavir 
Fosamprenavir 
pioglitazone  
Posaconazole 
Tofisopam 
Rifabutin 
Ritonavir 
Tipranavir 
Rifampin 
Saquinavir 
Verapamil 
Topiramate 
Telithromycin 
 
 
Troleandomycin 
 
 
Voriconazole 
 
 
This database of CYP inhibitors was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table and from the 
University of Washington’s Drug Interaction Database based on in vitro studies. Strong inhibitors are predicted to increase Abiraterone 
acetate AUC > 5-fold, and moderate inhibitors are predicted to increase Abiraterone AUC ≥ 2-fold but < 5-fold.  
This database of CYP inducers was compiled from the FDA’s “Guidance for Industry, Drug Interaction Studies;” from the Indiana University 
School of Medicine’s “Clinically Relevant” Table; and from (Pursche et al. 2008). 
 
Note: Site pharmacist or physician should review subject’s concomitant medication list while in screening and once 
on study for drug to drug interactions. This is a not an all-inclusive list.  
 
 
 
 
 
 
 
 
 
 
 

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CYP450 SUBSTRATES TO BE USED WITH CAUTION 
 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A4,5,7** 
amodiaquine 
celecoxib 
amitriptyline 
Adinazolam 
fentanyl2 
cerivastatin 
diclofenac 
citalopram 
alfentanil1,2 
flunitrazepam 
pioglitazone 
flurbiprofen 
clobazam 
alpha-
dihydroergocryptine1 
fluticasone1 
repaglinide 
fluvastatin 
clomipramine 
alprazolam 
lovastatin1 
rosiglitazone  
glibenclamide 
(glyburide) 
clopidogrel 
amlodipine 
maraviroc1 
torsemide 
gliclazide 
diazepam 
aripiprazole 
midazolam1 
troglitazone 
glimepiride 
fluoxetine 
atorvastatin 
nifedipine 
 
glipizide 
imipramine 
brotizolam1 
nisoldipine 
 
indomethacin 
lansoprazole 
budesonide1 
nitrendipine 
 
irbesartan 
moclobemide 
buspirone1 
perospirone1 
 
ketobemidone 
omeprazole 
cerivastatin 
quinine 
 
lornoxicam 
pantoprazole 
chlorpheniramine 
sildenafil1 
 
losartan 
progesterone 
cyclosporine2 
simvastatin1 
 
meloxicam 
propranolol 
darifenacin1 
sirolimus1,2 
 
naproxen 
quazepam 
Diazepam 
tipranavir1 
 
nateglinide 
rabeprazole 
diergotamine2 
trazodone 
 
piroxicam 
sertraline 
ebastine1 
triazolam1 
 
S-ibuprofen 
S-mephenytoin 
eletriptan1 
 
 
sulfamethoxazole 
 
eplerenone1 
 
 
tenoxicam 
 
ergotamine2 
 
 
tolbutamide 
 
Estazolam 
 
 
torsemide 
 
everolimus1 
 
 
valdecoxib 
 
 
 
* This database of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table, and from 
(Zhou et al. 2009) 
** CYP3A4,5,7 substrates were compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table; and supplemented by 
the FDA’s “Guidance for Industry, Drug Interaction Studies” and the University of Washington’s Drug Interaction Database. 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered with a potent 
inhibitor of the respective enzyme. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their exposure levels by the 
concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes). 
 
Note: Site pharmacist or physician should review subject’s concomitant medication list while in screening and once 
on study for drug to drug interactions. This is a not an all-inclusive list.  
 

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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 
Note: Site pharmacist or physician should review subject’s concomitant medication list while in screening and once 
on study for drug to drug interactions. This is a not an all-inclusive list.  

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APPENDIX 3:  NCI COMMON TOXICITY CRITERIA  
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 can be found here: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 

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APPENDIX 4:  CRITERIA FOR DISEASE PROGRESSION 
Prostate Cancer Clinical Trials Working Group 3 (PCWG3) Outcome Measures (13) 
  
 
Variable 
Prevent/Delay Endpoints 
PSA 
Decline from baseline: record time from start of 
therapy to first PSA increase that is ~25% and 
~2.0 ng/mL above the nadir, and which is 
confirmed by a second value 3 or more weeks later 
(i.e., a confirmed rising trend)† 
Recording the duration of PSA decline of little 
value 
No decline from baseline: PSA progression ~25% 
and ~2.0 ng/mL after 12 weeks 
Soft-tissue 
lesions 
Use RECIST criteria for progression, with 
additional requirement that progression at first 
assessment be confirmed by a second scan 6 or 
more weeks later 
Note that for some treatments, a lesion may 
increase in size before it decreases 
Bone 
The appearance of ~2 new lesions, and, for the 
first reassessment only, a confirmatory scan 
performed 6 or more weeks later that shows at 
least 2 or more additional new lesions 
The date of progression is the date of the first scan 
that shows the change