Clinical trial NCT01751451
Conditions: Prostate Cancer
Keywords: ABIRATERONE ACETATE (CB 7630) DEGARELIX PREDNISONE 12-187
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2012-12-18; Completion date: 2020-09-28
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In April 2011, the United States Food and Drug Administration (FDA) approved the oral drug abiraterone acetate (Zytiga ®) in combination with prednisone (a steroid) to treat patients with metastatic castration-resistant prostate cancer who have received prior docetaxel (chemotherapy). In December 2012, the FDA approved Zytiga ® in combination with prednisone to treat patients with metastatic castration-resistant prostate cancer who have not received prior chemotherapy. Degarelix (Firmagon ®), a testosterone lowering agent given as a monthly injection, is FDA approved for the treatment of patients with advanced prostate cancer. The purpose of this study is to evaluate abiraterone acetate and prednisone in combination with degarelix as a possible treatment for PSA recurrent prostate cancer as compared to abiraterone acetate alone and degarelix alone. This will be the first time these drugs will be used together.

Detailed description:

Arms: arm 1: Group 1

* Abiraterone acetate 1000 mg daily x 8 months
* Prednisone 5 mg once daily x 8 months arm 2: Group 2

Abiraterone acetate 1000 mg daily x 8 months

* Prednisone 5 mg once daily x 8 months
* Degarelix subcutaneous depot injection q 1 month x 8 months arm 3: Group 3

• Degarelix subcutaneous depot injection q 1 month x 8 months
Interventions: intervention 1: Abiraterone acetate intervention 2: Abiraterone acetate plus degarelix intervention 3: Degarelix
Intervention descriptions: intervention 1: Patients randomized to abiraterone acetate and prednisone (Group 1) will be instructed to take 1000 mg (four 250 mg tablets) of abiraterone acetate orally (PO) at least 1 hour before a meal and 2 hours after a meal every day. These patients will also be treated with prednisone 5 mg once daily with food. intervention 2: Patients randomized to abiraterone acetate plus degarelix and prednisone (Group 2) will be instructed to take 1000 mg (four 250 mg tablets) of abiraterone acetate orally (PO) at least 1 hour before a meal and 2 hours after a meal every day and prednisone 5 mg once daily with food. Patients will also be given two subcutaneous injections of degarelix 120 mg on Cycle 1, Day 1(starting dose) and 80 mg subcutaneous doses (maintenance doses) every 28 days (±3 days) thereafter. intervention 3: Patients randomized to degarelix alone (Group 3) will be given two subcutaneous injections of degarelix 120 mg on Cycle 1, Day 1 (starting dose) and 80 mg subcutaneous doses (maintenance doses) every 28 days (± 3 days) thereafter.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
1 of 69 
 
 
 
 
A phase 2, randomized, 3-arm study of abiraterone acetate alone, abiraterone acetate plus 
degarelix, a GnRH antagonist, and degarelix alone for patients with prostate cancer with a 
rising PSA or a rising PSA and nodal disease following definitive radical prostatectomy 
 
PCCTC LOI #: c11-092 
 
 
Lead Site: Memorial Sloan-Kettering Cancer Center 
 
Sponsor: Memorial Sloan-Kettering Cancer Center 
 
 
 
Principal Investigator 
Howard I. Scher, MD 
Service Chief, Genitourinary Oncology Service 
email: scherh@mskcc.org 
Statistician 
Glenn Heller, PhD 
Memorial Sloan-Kettering Cancer Center 
email: hellerg@mskcc.org 
Co-investigator 
Michael Morris, MD 
Associate Attending, Genitourinary Oncology Service 
email: morrism@mskcc.org 
Protocol Manager 
Ahkeem Simmons 
Prostate Cancer Clinical Trials Consortium 
email: simmona1@mskcc.org 
 
 
 
 
Participating Sites 
Principal Investigator 
Site’s Role 
Oregon Health and Science 
University, Knight Cancer Institute 
Julie Graff, MD 
Data Collection 
Rutgers Cancer Institute of New 
Jersey 
Tina Mayer, MD 
Data Collection 
North Shore University Health 
System 
Daniel Shevrin, MD 
Data Collection 
Duke University Medical Center 
Michael Harrison, MD 
Data Collection 
Northwestern University, Feinberg 
School of Medicine 
Timothy Kuzel, MD 
Data Collection 
Johns Hopkins University, The 
Sidney Kimmel Comprehensive 
Cancer Center 
Emmanuel Antonarakis, MD 
Data Collection 
University of North Carolina 
Matthew I. Milowsky, MD 
Data Collection 
Karmanos Cancer Institute, Wayne 
Ulka Vaishampayan, MD 
Data Collection 


2 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
 
State University 
Perlmutter New York University 
Cancer Center 
Arjun Balar, MD 
Data Collection 
Weill Cornell Medical Center 
Scott Tagawa, MD 
Data Collection 
GU Research Network 
Luke Nordquist, MD 
Data Collection 
 
 
 
 
 
 
Protocol Date: August 8, 2012 
Amended Version Date: October 22, 2012 
Amended Version Date: December 27, 2013 
Amended Version Date: August 11, 2014 
Amended Version Date: August 12, 2015 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, consultant, 
or contractor, for review by you, your staff, and the appropriate Institutional Review Board or Ethics 
Committee. By accepting this document, you agree that the information contained herein will not be 
disclosed to others without written authorization from the lead site, except to the extent necessary to 
initiate the study or conduct study-related activities. 


3 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
 
INVESTIGATOR’S APPROVAL OF PROTOCOL 
 
 
 
 
Title: 
A phase 2, randomized, 3-arm study of abiraterone acetate alone, 
abiraterone acetate plus degarelix, a GnRH antagonist, and degarelix 
alone for patients with prostate cancer with a rising PSA or a rising 
PSA and nodal disease following definitive radical prostatectomy 
 
 
 
 
 
 
 
 
Principal                                             Investigator                                             Signature: 
 
 
 Principal 
Investigator                                          
Print: 
  
 
Date: 


4 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
PROTOCOL SUMMARY 
Title 
A phase 2, randomized, 3-arm study of abiraterone acetate alone, abiraterone 
acetate plus degarelix, a GnRH antagonist, and degarelix alone for patients with 
prostate cancer with a rising PSA or a rising PSA and nodal disease following 
definitive radical prostatectomy 
Lead site 
Memorial Sloan-Kettering Cancer Center 
Sponsor 
Memorial Sloan-Kettering Cancer Center 
Investigational agent 
Abiraterone acetate (Janssen Scientific Affairs, LLC) 1000 mg (four 250 mg 
tablets) daily plus prednisone 5 mg once daily; abiraterone acetate plus prednisone 
with once monthly degarelix injection or; once monthly degarelix injection only. 
Phase 
Phase 2 
Target population 
Post-radical prostatectomy men with a serum testosterone of 150 ng/dL or greater 
who now have a rising PSA and a PSADT ≤ 9 months without metastatic disease. 
However, patients with pelvic and/or retroperitoneal nodes < 2 cm in short axis 
will be permitted on study, as they are considered not to have definitive 
metastases. 
Start date/Duration 
It is anticipated that the trial will remain open to accrual for 36 months with an 
additional 18 month follow-up after accrual closure. 
Expected enrollment 
120 patients 
Rationale 
Our central hypothesis is that the increased androgen suppression achieved with 
abiraterone acetate can eliminate disease that has recurred after radical 
prostatectomy with or without post-operative radiation therapy. 
The objective of this protocol is to study whether the abiraterone acetate, alone or 
in combination with a gonadotropin-releasing hormone antagonist can potentially 
cure a proportion of men with non-castrate testosterone levels after radical 
prostatectomy and now have a rising PSA and a PSADT ≤ 9 months without 
definitive metastatic disease. The initial screening endpoint to determine whether 
the approach is worthy of further study is an undetectable PSA with non-castrate 
levels of testosterone at 18 months from the time of  treatment initiation (PSA0). 
Androgen depletion and/or blockade currently practiced with degarelix, a GnRH 
agonist/antagonist with or without an antiandrogen produces declines in PSA 
followed by tumor shrinkage, a period of quiescence during which the disease does 
not proliferate, followed by a rise in PSA and regrowth as a castration-resistant 
prostate cancer (CRPC) that for most men is invariably lethal. Androgen depletion 
as traditionally utilized does not completely inhibit androgen responsive gene 
expression (PSA, etc.),1 it does not consistently produce levels of testosterone 
below 20 ng/dL,2-4 and does not completely eradicate disease due to the presence 
of cells that can resist and/or survive in a low androgen environment when the 
disease is first manifest clinically.5 Overall outcomes with ADT are inversely 
related to disease burden and the results of multiple series show that patients with 


5 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
more advanced disease progress and die sooner in comparison to those with less 
advanced disease.6,7 Even in the neoadjuvant setting where the disease is clinically 
confined to the gland, prostates removed after 3 months or up to 8 months of 
treatment are rarely tumor-free.8 
We hypothesize that abiraterone-based treatments will be superior to androgen 
depletion with degarelix alone, and potentially cure (primary endpoint: 
progression-free survival at 18 months from the time of randomization) a 
proportion of men with a rising PSA and a rapid PSADT without definitive 
metastatic disease following radical prostatectomy. The potential clinical benefit of 
the approach under study includes the potential for cure, as well as the avoidance 
of repeated cycles of hormone therapy treatment, each of which is associated with 
short term and long term toxicities, some of which are cumulative. 
The study is focused on men with a rising PSA and rapid PSADTs without 
definitive metastatic disease who are at risk for prostate cancer-specific morbidity 
and mortality.9-11 This restriction limits therapy to those who require it, and builds 
on results in other tumor types where therapies that have shown activity in more 
advanced disease settings can cure a proportion of patients in the adjuvant setting 
with micrometastatic disease.12-16 
The treatment regimen are easily administered and safe, build on established 
standards of care, and offer the highest probability of demonstrating  clinical 
benefit in a short time frame. Three treatment groups will be studied: abiraterone 
acetate alone, abiraterone acetate plus degarelix, and degarelix alone. We have 
selected degarelix to avoid the initial serum testosterone elevations that occur with 
GnRH agonists/antagonists which are not completely blocked with the currently 
available anti-androgens.3,17 Degarelix treatment reduces serum androgen levels to 
a castrate range within 48 hours.18 
Study design 
A randomized phase 2 screening design is used to compare the efficacy of 
abiraterone acetate and abiraterone acetate plus degarelix to degarelix alone for 
prostate cancer patients in the rising PSA clinical state. 
After obtaining informed consent, patients who satisfy the eligibility requirements 
will be randomized prospectively: 
Arm 1 
• Abiraterone acetate 1000 mg daily x 8 months 
• Prednisone 5 mg once daily x 8 months 
Arm 2 
• Abiraterone acetate 1000 mg daily x 8 months 
• Prednisone 5 mg once daily x 8 months 
• Degarelix subcutaneous depot injection(s) q 1 month x 8 months 
Arm 3 
• Degarelix subcutaneous depot injection(s) q 1 month x 8 months 
Criteria for 
Primary endpoint: 
The primary endpoint for each cohort is progression-free survival (PFS) at 18 


6 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
evaluation 
months from the start of treatment initiation (PSA0). PFS is defined as an 
undetectable PSA (at the institution of participant registration) with a non-castrate 
level of testosterone (>150 ng/dL). Pathological lymph nodes (whether target or 
non‐target) must also have reduction in short axis to <10 mm (Complete Response 
per RECIST) in order to meet the criteria for PFS. 
Secondary endpoints: 
• PSA response rate (Percentage of patients with an undetectable PSA at 8 months 
from PSA0). 
• Effects of each arm on overall quality of life, with particular attention to libido, 
potency, anxiety, depression, hot flashes, and fatigue. 
• Frequency and intensity of non-hematologic adverse events. 
• Testosterone and leuteinizing hormone (LH) recovery rates. 
Tertiary endpoint: 
• Correlative tissue analysis with clinical outcomes while on study treatment. 
Statistical method 
One hundred and twenty patients will be randomized to the three treatment groups. 
Each abiraterone acetate group will be compared to the degarelix alone group. 
With 40 patients per group, it is assumed that the probability of a success in the 
degarelix alone group is ≤ 0.25 and the probability of a success is at least 0.20 
greater than degarelix alone in the abiraterone acetate-based groups. Under these 
projections, there is greater than an 80% chance of finding for either abiraterone 
acetate-based treatment relative to degarelix alone using Fisher’s exact test with a 
one-sided 0.20 significance level. 
The choice of a 0.20 significance level is intended to reduce the sample size required 
for this comparative study. A significant outcome does not imply definitive evidence 
of superiority for either abiraterone acetate-based treatment relative to degarelix 
alone due to this high type 1 error, but instead provides sufficient evidence that 
testing of abiraterone acetate should proceed to a large-scale randomized phase 3 
study in this patient population. 
Safety analysis 
Safety analysis will be summarized using the Safety Population defined as any 
patient receiving any part of study treatment. 
Extent of exposure to study treatment will be summarized and details will be 
provided. Treatment emergent adverse events (AEs) are those events that occur or 
worsen on or after first dose of study drug up through 30 days post last dose. 
Adverse events will be coded using the MedDRA coding system and all AEs will 
be graded according to the most current National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE). 


7 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................................................................... 9 
1.1 
Disease Background................................................................................................................................................................9 
1.2 
Rising PSA Clinical State .....................................................................................................................................................9 
1.3 
Androgen Depletion and/or Blockade for PSA Progression .................................................................................. 10 
1.4 
Abiraterone Acetate.............................................................................................................................................................. 11 
1.5 
Clinical Benefits of Proposed Treatment ...................................................................................................................... 18 
1.6 
Rationale for Therapeutic Intervention ......................................................................................................................... 18 
1.7 
Choice of Undetectable PSA as the Primary Endpoint ............................................................................................ 18 
2. 
OBJECTIVES ............................................................................................................................................................... 19 
2.1 
Primary Objective ................................................................................................................................................................. 19 
2.2 
Secondary Objectives .......................................................................................................................................................... 19 
3. 
PATIENT SELECTION ............................................................................................................................................. 19 
3.1 
Target Population .................................................................................................................................................................. 19 
3.2 
Inclusion Criteria ................................................................................................................................................................... 19 
3.3 
Exclusion Criteria ................................................................................................................................................................. 20 
4. 
PATIENT REGISTRATION ..................................................................................................................................... 22 
4.1 
Lead Center (MSKCC) Registration .............................................................................................................................. 22 
4.2 
Institutional Registration .................................................................................................................................................... 23 
5. 
STUDY TREATMENTS ............................................................................................................................................ 23 
5.1 
Description of Treatments ................................................................................................................................................. 23 
5.2 
Treatments Administered ................................................................................................................................................... 24 
5.3 
Selection and Timing of Dose for Each Patient ......................................................................................................... 24 
5.4 
Randomization ....................................................................................................................................................................... 24 
5.5 
Concomitant Medications .................................................................................................................................................. 25 
5.6 
Packaging and Labeling ...................................................................................................................................................... 26 
5.7 
Storage and Accountability ................................................................................................................................................ 27 
5.8 
Criteria for Discontinuation of Study Treatment ....................................................................................................... 27 
5.9 
Criteria for Discontinuation of Post-Treatment Follow-Up ................................................................................... 28 
6. 
STUDY PROCEDURES ............................................................................................................................................. 28 
6.1 
Informed Consent.................................................................................................................................................................. 31 
6.2 
Medical History ..................................................................................................................................................................... 31 
6.3 
Physical Examination .......................................................................................................................................................... 31 
6.4 
Cardiac Function ................................................................................................................................................................... 31 
6.5 
Clinical laboratory Tests ..................................................................................................................................................... 32 
6.6 
Efficacy/Response Assessments ...................................................................................................................................... 32 
6.7 
Testosterone and Luteinizing Hormone Recovery Rates ........................................................................................ 32 
6.8 
Patient-reported Outcomes ................................................................................................................................................ 32 
6.9 
Safety Evaluation .................................................................................................................................................................. 33 
6.10 Correlative Studies ............................................................................................................................................................... 33 
7. 
STUDY ACTIVITIES ................................................................................................................................................. 33 
7.1 
Within 30 Days Prior to Protocol Therapy Initiation ................................................................................................ 33 
7.2 
Within 14 Days Prior to Protocol Therapy Initiation ................................................................................................ 34 
7.3 
Treatment Period (Day 1 ±3 days to Week 32 ± 3 days) ......................................................................................... 34 
7.4 
Post-treatment Follow-up ................................................................................................................................................... 36 
8. 
ADVERSE EVENTS ................................................................................................................................................... 36 
8.1 
Definitions ............................................................................................................................................................................... 36 
8.2 
Management of Adverse Events, Serious Adverse Events and Special Reporting Situations .................... 38 
8.3 
Recording of Adverse Events, Serious Adverse Events and Special Reporting Situations ......................... 38 
8.4 
Grading Adverse Events ..................................................................................................................................................... 39 


8 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
9. 
TREATMENT EVALUATION AND OUTCOMES ............................................................................................ 44 
9.1 
Primary Endpoint .................................................................................................................................................................. 44 
9.2 
Secondary Endpoints ........................................................................................................................................................... 45 
9.3 
Tertiary Endpoint .................................................................................................................................................................. 45 
10. 
DATA REPORTING AND REGULATORY REQUIREMENTS .................................................................... 45 
10.1 Data Collection and Management .................................................................................................................................... 45 
10.2   Study Monitoring and Quality Assurance ..................................................................................................................... 46 
11. 
STATISTICAL METHODS ....................................................................................................................................... 48 
11.1 General Considerations ....................................................................................................................................................... 48 
11.2 Sample Size Determination................................................................................................................................................ 48 
11.3 Analysis Population.............................................................................................................................................................. 48 
11.4 Demographics and Baseline Characteristics ................................................................................................................. 49 
11.5 Safety Analysis ...................................................................................................................................................................... 49 
12. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS ................................................................... 49 
12.1 Roles and Responsibilities ............................................................................................................................................... 49 
12.2   Ethical Considerations ......................................................................................................................................................... 50 
12.3   Regulatory Documentation .............................................................................................................................................. 50 
12.4   Protocol Amendments .......................................................................................................................................................... 51 
12.6 Written Informed Consent .................................................................................................................................................. 52 
12.7 Protection of Privacy ............................................................................................................................................................ 52 
12.8 Terminating or Modifying the Study .............................................................................................................................. 52 
13. 
REFERENCES ........................................................................................................................................................................ 53 
APPENDIX A: ECOG PERFORMANCE STATUS SCALE ........................................................................................ 56 
APPENDIX B: PRO SURVEY .............................................................................................................................................. 57 
APPENDIX C: JANSSEN SERIOUS ADVERSE EVENT REPORT FORM (FOR PCCTC) .............................. 61 
APPENDIX D: PCCTC SAE REPORT FORM FOR ALL SITES .............................................................................. 65 
APPENDIX E: GLOSSARY OF ABBREVIATIONS AND ACRONYMS ................................................................ 66 


9 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
1. 
INTRODUCTION 
1.1 
Disease Background 
The course of prostate cancer from diagnosis to death can be categorized as a series of clinical 
states (Figure 1) based on the status of the primary tumor, presence or absence of visible 
metastatic disease on an imaging study, and the measured level of testosterone in the blood.19 The 
states are localized disease, rising levels of prostate-specific antigen (PSA) after radiation therapy 
or surgery with no detectable metastases, and clinical metastases in the non-castrate or castrate 
state. 
Figure 1. Clinical states of prostate cancer 
 
 
 
 
 
Clinically 
Localized 
Disease 
2 
Clinical 
Metastases: 
 
Pre- 
Provenge 
Abiraterone 
 
3 
Clinical 
Metastases: 
Castrate 
1st Line 
Docetaxel 
 
 
Neoadjuvant 
Adjuvant 
 
1.2 
Rising PSA Clinical State 
Although surgery, radiation, or a combination of both can be curative for patients with localized 
disease, a significant proportion of these patients have recurrent disease as evidenced first by a 
rising level of PSA. For these individuals, the issue is to determine whether the disease is local or 
systemic, and if the later, the risk of developing metastatic disease – a transition to the lethal 
phenotype of the illness and in what time frame.  A number of nomograms based on the 
characteristics of the primary tumor, time to a detectable PSA following surgery, and rate of rise 
in PSA or PSA doubling time (PSADT) have been developed to estimate prognosis, which for the 
group as a whole is heterogeneous.20-24 
In one series of patients with rising PSA enrolled on clinical protocols (N = 148) PSADT was a 
statistically significant independent predictor for metastatic progression (P = 0.001).25   Moreover, 
a shorter PSADT is significantly associated with prostate cancer-specific and all-cause mortality 
with virtually all men who ultimately die of the disease having a PSADT of 3 months or less.26,27 
In practice, most men with a PSADT of 12 months or less are treated, but we are restricting 
eligibility to men with a PSADT of 9 months or less based on the recently reported metastases 
free survival times in a contemporary series (Table 1). 
Table 1. Metastasis-free survival (MFS) after PSA recurrence according to PSADT  
 
PSADT < 3 mos 
(N = 46) 
PSADT 3-9 mos 
(N = 106) 
PSADT 9-15 mos 
(N = 86) 
PSADT ≥ 15 mos 
(N = 212) 
Median MFS, years 
(95% CI) 
1 (0,1) 
4 (2,4) 
13 (6, >15) 
15 (15, >17) 
Metastasis-free rate at 
5 years, % (95% CI) 
5 (1, 21)* 
27 (16, 39) 
77 (63, 86) 
91 (85, 95) 
Metastasis-free rate at 
10 years, % (95% CI) 
N/A 
7 (1, 22) 
51 (34, 66) 
72 (59, 83) 
*Last subject censored at 4 years. In each subgroup, the median MFS as well as the 5- and 10-year probabilities of 
MFS from the time of PSA recurrence are shown. N/A, not applicable. 
Clinical 
Metastases: 
Non-Castrate 
4 
Clinical 
Metastases: 
Post- 
Cabazitaxel 
Abiraterone 
Rising 
PSA 
1 
Rising PSA: 
Castrate 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
10 of 69 
 
 
In this series, 73% of men with a PSADT in the range of 3-9 months, and 95% of men with a 
PSADT of less than 3 months developed visible metastatic disease at 5 years. 
 
We are also including men with visible pelvic and/or retroperitoneal nodes < 2 cm in short axis, 
as nodal disease at this site of spread is particularly sensitive to and will often completely regress 
on androgen depletion therapy, and will not recur at the time of relapse. 
 
1.3 
Androgen Depletion and/or Blockade for PSA Progression 
Androgen depletion and/or blockade (ADT) as currently practiced with a gonadotropin-releasing 
hormone (GnRH) agonist/antagonist with or without an antiandrogen produces declines in PSA 
followed by tumor shrinkage, a period of quiescence during which the disease does not 
proliferate, followed by a rise in PSA and regrowth as a castration-resistant prostate cancer 
(CRPC) that for most men is invariably lethal. Overall outcomes are inversely related to disease 
burden and the results of multiple series show that patients with more advanced disease progress 
sooner in comparison to those with less advanced disease.6,7 
We hypothesize that abiraterone-based treatments will be superior to androgen depletion with 
degarelix alone, and potentially cure (primary endpoint: progression-free survival at 18 months 
from the time of randomization) a proportion of men with a rising PSA and a PSADT ≤ 9 months 
without definitive metastatic disease following radical prostatectomy. 
 
1.3.1 
ADT does not completely suppress androgen signaling 
Androgen depletion as traditionally utilized does not completely inhibit androgen 
responsive gene expression (PSA, etc.),1 it does not consistently produce levels of 
testosterone below 20 ng/dl,2-4 and does not completely eradicate disease due to the 
presence of cells that can resist and/or survive in a low androgen environment when the 
disease is first manifest clinically.5 Overall outcomes with ADT are inversely related to 
disease burden and the results of multiple series show that patients with more advanced 
disease progress and die sooner in comparison to those with less advanced disease.6,7 
Even in the neoadjuvant setting where the disease is clinically confined to the gland, 
prostates removed after 3 months or up to 8 months of treatment are rarely tumor-free.8 
To understand the mechanisms contributing to treatment resistance, we performed  
mRNA expression profiles of prostate cancers representing untreated and post-hormone 
treated primary tumors, and castration resistant metastatic disease. In pre-prostatectomy 
hormone treated patients, we found that androgen receptor (AR) gene expression in the 
residual tumor in the prostate after 3 months of ADT alone was reduced but persistent and 
many of the post-hormone treated samples continued to express AR target genes such as 
PSA, prostatic acid phosphatase, prostate specific transglutaminase (TGP), KLK1, and 
TMPRSS2.1 An association was shown between the level of PSA mRNA and protein 
expression and biochemical relapse.28 The finding that intratumoral androgen levels are 
only reduced by 75% following conventional ADT, at the time when androgen levels in 
the blood are in the castrate range,29 may explain in part, the failure to eliminate disease 
completely in the primary site. In 1979, Geller and colleagues first demonstrated 
increased intratumoral androgens in the prostates of men who had undergone castration,30 
a finding confirmed by others. Adrenal androgen synthesis was the postulated source, 
although a failure to completely suppress androgen production could not be excluded.29,31- 
33 Subsequently, Holzbeierlein et al1 reported an up to 5-fold induction of several enzymes 
involved in steroid hormone production, also confirmed by others,34,35                         
suggesting the possibility of intratumoral production of androgens as the primary source. 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
Intermittent hormone therapy as a therapeutic option 
1.3.2 
11 of 69 
 
 
Most of the approvals for the hormonal therapies to treat prostate cancer have been on the 
basis of an equivalent effect on serum testosterone levels, or an improved safety profile 
relative to other available agents.36-38 None have shown superiority in a cancer specific 
outcome such as an improvement in disease related symptoms, time to progression or 
overall survival. Recently, a Canadian study comparing intermittent vs. continuous 
therapy was reported which showed no difference in cancer specific outcomes, but a 
marked improvement in overall quality of life for men treated on the intermittent 
approach.39 Other groups have explored the approach with “on cycles” of varied duration, 
but in most studies, the maximal response is observed by 8 months, which is duration of 
therapy we have selected for the current study.40 
1.3.3 
Time to testosterone recovery 
The incidence of, and length of time to recovery tends to decline with subsequent off- 
treatment cycles and is a function of longer treatment schedules, lower pretreatment 
baseline PSA testosterone levels, and advancing age.41 Overall, testosterone levels return 
to a non-castrate range with 6 months of stopping treatment in 75% of cases (Figure 2). 
 
 
Figure 2. Recovery of testicular function after androgen suppression. 
The proportion of patients with serum testosterone levels ≥7.5 nmol/l is plotted as a function of time 
after the interruption of androgen withdrawal therapy. These results show that testosterone recovery 
occurs in many patients, especially in the first off-treatment phase.41 
 
1.4 
Abiraterone Acetate 
Abiraterone acetate is a steroidal inhibitor of CYP17 that blocks two important enzymatic 
activities in the synthesis of testosterone. It was developed originally for use in the non-castrate 
hormone naïve (non-castrate) setting, an indication that was largely abandoned after an initial 
proof of concept trial. Of particular interest was the demonstration that abiraterone acetate 
treatment resulted in testosterone levels to the 1-2 ng/dL range which is significantly lower than 
the20-30 ng/dL range achieved with conventional androgen-depletion with a surgical 
orchiectomy or GnRH agonist/antagonist with or without an antiandrogen.42 The maximal dose 
administered in the trial was 750 mg daily, below the currently approved 1000 mg dose. 
 
In April 2011, the FDA approved abiraterone acetate for use in combination with prednisone for 
the treatment of patients with metastatic CRPC who have received prior chemotherapy 
containing docetaxel. In December 2012, the FDA approved abiraterone acetate for use in 


12 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
combination with prednisone for the treatment of patients with metastatic CRPC who have not yet 
 
 
received chemotherapy. 
 
1.4.1 Description and mechanism of action 
Pharmacology 
Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis 
inhibitor, that inhibits 17 α-hydroxylase/C17, 20-lyase (CYP17). This enzyme is 
expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen 
biosynthesis. 
 
CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and 
progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the 
subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, 
respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and 
are precursors of testosterone. 
 
Pharmacokinetics and Metabolism 
Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and 
abiraterone acetate have been studied in healthy subjects and in patients with metastatic 
CRPC. In vivo, abiraterone acetate is converted to abiraterone. In clinical studies, 
abiraterone acetate plasma concentrations were below detectable levels (< 0.2 ng/mL) in 
> 99% of the analyzed samples. 
 
Following oral administration of abiraterone acetate to patients with metastatic CRPC, 
the median time to reach maximum plasma abiraterone concentrations is 2 hours. 
Abiraterone accumulation is observed at steady-state, with a 2-fold higher exposure 
(steady-state AUC) compared to a single 1000 mg dose of abiraterone acetate. 
 
At the dose of 1000 mg daily in patients with metastatic CRPC, steady-state values (mean 
± SD) of Cmax were 232 ± 177 ng/mL and of AUC were 1060 ± 681 ng.hr/mL. No major 
deviation from dose proportionality was observed in the dose range of 250 mg to 1000 
mg. 
 
Systemic exposure of abiraterone is increased when abiraterone acetate is administered 
with food. Abiraterone Cmax and AUC0-∞ were approximately 7- and 5-fold higher, 
respectively, when abiraterone acetate was administered with a low-fat meal (7% fat, 300 
calories) and approximately 17- and 10-fold higher, respectively, when abiraterone 
acetate was administered with a high-fat (57% fat, 825 calories) meal. 
 
1.4.2 
Warnings and precautions 
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess 
Use abiraterone acetate with caution in patients with a history of cardiovascular disease. 
Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a 
consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see 
Adverse Reactions (1.4.3) and Description of Mechanisms of Action (1.4.1)]. Co- 
administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, 
resulting in a reduction in the incidence and severity of these adverse reactions. Use 
caution when treating patients whose underlying medical conditions might be 
compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those 
with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of 


13 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
abiraterone acetate in patients with left ventricular ejection fraction <50% or NYHA  
Class III or IV heart failure has not been established because these patients were excluded 
from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and 
fluid retention at least once a month. Control hypertension and correct hypokalemia 
before and during treatment with abiraterone acetate. 
 
Adrenocortical Insufficiency 
Adrenocortical insufficiency has been reported in clinical trials in patients receiving 
abiraterone acetate in combination with prednisone, following interruption of daily 
steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms 
and signs of adrenocortical insufficiency, particularly if patients are withdrawn from 
prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and 
signs of adrenocortical insufficiency may be masked by adverse reactions associated   
with mineralocorticoid excess seen in patients treated with abiraterone acetate. If 
clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical 
insufficiency. Increased dosage of corticosteroids may be indicated before, during and 
after stressful situations [see Warnings and Precautions (1.4.2)]. 
 
Hepatotoxicity 
Marked increases in liver enzymes leading to drug discontinuation or dosage 
modification have occurred [see Adverse Reactions (1.4.2)]. Measure serum 
transaminases (ALT and AST) and bilirubin levels prior to starting treatment with 
abiraterone acetate, every two weeks for the first three months of treatment and monthly 
thereafter. In patients with baseline moderate hepatic impairment receiving a reduced 
abiraterone acetate dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of 
treatment, every week for the first month, every two weeks for the following two months 
of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and 
ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of 
AST, ALT, or bilirubin from the patient's baseline should prompt more frequent 
monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin 
rises above three times the ULN, interrupt abiraterone acetate treatment and closely 
monitor liver function. 
 
Re-treatment with abiraterone acetate at a reduced dose level may take place only after 
return of liver function tests to the patient’s baseline or to AST and ALT less than or 
equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Study 
Treatments (5)]. 
 
The safety of abiraterone acetate re-treatment of patients who develop AST or ALT 
greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is 
unknown. 
 
Food Effect 
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 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 [see Study Treatments (5) and Mechanism of Action 
(1.4.1)]. 


14 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
1.4.3 
Adverse reactions 
Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in the clinical trials of a drug cannot be directly compared to rates in the 
clinical trials of another drug and may not reflect the rates observed in clinical practice. 
 
In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic 
castration-resistant prostate cancer who were using a gonadotropin-releasing hormone 
(GnRH) agonist or were previously treated with orchiectomy, but had no prior 
chemotherapy (COU-AA-302), abiraterone acetate was administered at a dose of 1,000 
mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N 
= 546). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 
542). The median duration of treatment with abiraterone acetate was 13.8 months and 
was 8.3 months in the placebo plus prednisone group. 
 
The most common adverse drug reactions (≥10% of subjects in any treatment group) 
reported in two large, randomized, double-blind, placebo-controlled Phase 3 abiraterone 
acetate studies (COU-AA-301 and COU-AA-302) were fatigue (44%), back pain (33%), 
nausea (28%), arthralgia (30%), constipation (26%), bone pain (24%), peripheral edema 
(26%), hot flush (21%), and diarrhea (21%). Most events were of Grade 1 or 2 toxicity. 
Noteworthy exceptions include muscle spasms, upper respiratory tract infection, 
hypertension, and increased alanine aminotransferase (ALT), all of which were reported 
at higher rates in COU-AA-302 compared with COU-AA-301. 
 
For the combined treatment groups, the most common adverse drug reactions that 
resulted in drug discontinuation were disease progression, spinal cord compression, back 
pain, aspartate aminotransferase increased, and alanine aminotransferase increased. In 
COU-AA-302, ALT increased was the most commonly reported AE leading to treatment 
discontinuation (1.7% of subjects in the abiraterone acetate group and 0.2% of subjects in 
the placebo group). 
 
Adverse events of special interest with abiraterone acetate therapy include fluid 
retention/edema, hypokalemia, hypertension, cardiac disorders, and hepatotoxicity. AEs 
of special interest were reported more commonly in patients treated with abiraterone 
acetate (61% of combined subjects in phase 3 trials) than in patients treated with placebo 
(48%). Events of hypokalemia were reported in 18% of subjects in the abiraterone acetate 
group versus 9% of subjects in the placebo group for study COU-AA-301; for study 
COU-AA-302, these proportions were 17% and 13%, respectively (see Table 2). 
 
In patients treated with abiraterone acetate, grades 3 to 4 hypokalemia occurred in 5% of 
patients in the COU-AA-301 study and 3% of patients in the COU-AA-302 study. Grades 
3 to 4 hypertension was reported in 1% of patients in COU-AA-301 and 4% of patients in 
COU-AA-302 [see Warnings and Precautions (1.4.2)]. 
 
Table 2 shows adverse reactions due to abiraterone acetate that occurred with either a ≥ 
1% absolute increase in frequency compared to placebo, or were events of special interest 
(mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). 


15 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
Table 2. Adverse reactions due to abiraterone acetate in a placebo-controlled phase 3 trial 
 
Abiraterone acetate 
with Prednisone 
(N=791) 
 
Placebo with Prednisone 
(N=394) 
 
System/Organ Class 
 
Adverse reaction 
All Grades1 
 
% 
 
Grade 3-4 
 
% 
 
All Grades 
 
% 
 
Grade 3-4 
 
% 
 
 
Musculoskeletal and connective tissue disorders 
 
Joint swelling/discomfort2 
29.5 
4.2 
23.4 
4.1 
Muscle discomfort3 
26.2 
3.0 
23.1 
2.3 
General disorders 
Edema4 
26.7 
1.9 
18.3 
0.8 
Vascular disorders 
 
Hot flush 
19.0 
0.3 
16.8 
0.3 
Hypertension 
8.5 
1.3 
6.9 
0.3 
Gastrointestinal disorders 
Diarrhea 
17.6 
0.6 
13.5 
1.3 
Dyspepsia 
6.1 
0 
3.3 
0 
Infections and infestations 
Urinary tract infection 
11.5 
2.1 
7.1 
0.5 
Upper respiratory tract infection 
5.4 
0 
2.5 
0 
Respiratory, thoracic and mediastinal disorders 
 
Cough 
10.6 
0 
7.6 
0 
 
Renal and urinary disorders 
 
Urinary frequency 
7.2 
0.3 
5.1 
0.3 
Nocturia 
6.2 
0 
4.1 
0 
Injury, poisoning and procedural complications 
Fractures5 
5.9 
1.4 
2.3 
0 
 
Cardiac disorders 
 
Arrhythmia6 
7.2 
1.1 
4.6 
1.0 
Chest pain or chest discomfort7 
3.8 
0.5 
2.8 
0 


16 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
Cardiac failure8 
2.3 
1.9 
1.0 
0.3 
1 Adverse events graded according to CTCAE version 3.0 
2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 
3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 
4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 
5 Includes all fractures with the exception of pathological fracture 
6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, 
Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 
7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the 
placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 
8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, 
Cardiomyopathy, and Ejection fraction decreased 
 
 
Cardiovascular Adverse Reactions 
Cardiovascular adverse reactions in the phase 3 trial are shown in Table 2. The majority 
of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the 
two arms. There was one death associated with arrhythmia and one patient with sudden 
death in the abiraterone acetate arm. No patients had sudden death or arrhythmia 
associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led 
to death in 2 patients in the placebo arm and 1 death in the abiraterone acetate arm. 
Cardiac failure resulting in death occurred in 1 patient on both arms. 
 
Hepatotoxicity 
Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been 
reported in patients treated with abiraterone acetate. Across all clinical trials, liver 
function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of 
patients who received abiraterone acetate, typically during the first 3 months after starting 
treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were 
more likely to experience liver function test elevations than those beginning with normal 
values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X 
ULN were observed, abiraterone acetate was withheld or discontinued. In two instances 
marked increases in liver function tests occurred [see Warnings and Precautions   
(1.4.2)]. These two patients with normal baseline hepatic function, experienced          
ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X                   
ULN. Upon discontinuation of abiraterone acetate, both patients had normalization of 
their liver function tests and one patient was re-treated with abiraterone acetate without 
recurrence of the elevations. 
 
In clinical trials, the following patients were excluded: patients with active hepatitis, 
patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, 
and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. 
Abnormal liver function tests developing in patients participating in clinical trials were 
managed by treatment interruption, dose modification and/or discontinuation [see Study 


17 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
Treatments (5) and Warnings and Precautions (1.4.2)]. Patients with elevations of ALT 
or AST > 20X ULN were not re-treated. 
 
Other Adverse Reactions 
Adrenal insufficiency occurred in two patients on the abiraterone acetate arm of the phase 
3 clinical trial (< 1%). 
 
Laboratory Abnormalities of Interest 
Table 3 shows laboratory values of interest from the phase 3 placebo-controlled 
clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred 
more frequently in the abiraterone acetate arm. 
 
Table 3. Laboratory abnormalities of interest in a phase 3 placebo-controlled clinical trial 
Abiraterone (N=791) 
Placebo (N=394) 
 
Laboratory Abnormality 
All Grades 
% 
Grade 3-4 
% 
All Grades 
% 
Grade 3-4 
% 
High Triglyceride 
62.5 
0.4 
53.0 
0 
High AST 
30.6 
2.1 
36.3 
1.5 
Low Potassium 
28.3 
5.3 
19.8 
1.0 
Low Phosphorus 
23.8 
7.2 
15.7 
5.8 
High ALT 
11.1 
1.4 
10.4 
0.8 
High Total Bilirubin 
6.6 
0.1 
4.6 
0 
 
 
1.4.4 
Clinical development of abiraterone in castration resistant disease 
The known effects of abiraterone on adrenal androgen biosynthesis led to a series of 
studies in pre-chemotherapy CRPC patients with significant and in many cases durable 
responses.43 Trials in post-chemotherapy CRPC followed with similar results.44 This lead 
to a phase 3 program in which abiraterone acetate plus prednisone was compared to 
placebo plus prednisone in the post-chemotherapy (Cougar-AA-301) setting, which 
showed a significant survival benefit,45 and pre-chemotherapy (Cougar-AA-302), which 
showed an improvement in radiographic progression-free survival and a trend toward 
improved overall survival.53 
1.4.5 
Development of abiraterone in non-castrate disease 
 
A proof of concept phase 1 trial conducted at the Royal Marsden showed that a dose of 
800 mg daily produced testosterone levels of 0.77 nmol/l which, in one patient, was not 
sustained due an increase in luteinizing hormone (LH) levels.46 The currently approved 
dose of 1000 mg daily was not evaluated. Subsequent profiling studies of human primary 
prostate carcinomas showed that a proportion of non-castrate primary tumors have 
increased expression of the enzymes in androgen biosynthetic pathway including 
CYP17,1,33,34,47 while a second study showed that CYP17A1 gene expression was 
upregulated in high risk, high grade, primary prostate tumors.48 
1.4.6 
Abiraterone acetate in combination with lupron, a GnRH agonist/antagonist increases 
response in the primary tumor 
Based on these findings, Investigators at the Dana-Farber Cancer Institute and the Fred 
Hutchinson Cancer Center are conducting a prospective trial in which patients receive 
either Lupron (leuprolide acetate) alone or Lupron plus abiraterone acetate plus 


18 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
prednisone for 12 weeks followed by a repeat biopsy to assess intratumoral androgen 
levels and androgen regulated gene expression. Both groups then receive 12 weeks of 
Lupron plus abiraterone acetate plus prednisone followed by a radical prostatectomy. 
Specimens are then assessed for pathologic response, intratumoral androgen, and AR 
regulated gene expression. To date, the majority of patients enrolled have been high risk 
and dramatic antitumor responses seen, which suggests that the additional 1 log reduction 
in androgen levels by abiraterone acetate can increase response rates (personal 
communication, M. Taplin). 
 
1.5 
Clinical Benefits of Proposed Treatment 
The potential clinical benefit of the approach under study includes the potential for cure, as well 
as the avoidance of repeated cycles of hormone therapy treatment, each of which is associated 
with short term and long term toxicities, some of which are cumulative. We are focused on men 
with a rising PSA and a PSADT ≤ 9 months without definitive metastatic disease, who are at risk 
for prostate cancer-specific mortality.9-11 Patients with pelvic and/or retroperitoneal nodes < 2 cm 
in short axis will be permitted on study, as they are considered not to have definitive metastases. 
The focus on men who require treatment because of their risk of prostate cancer-specific 
morbidity and morbidity restricts therapy to those who require it. This approach builds on results 
in other tumor types where therapies that have shown activity in more advanced disease settings 
can cure a proportion of patients in the easily monitored adjuvant micrometastatic setting.12-16. 
1.6 
Rationale for Therapeutic Intervention 
Men with a rising PSA following radical prostatectomy are motivated and want treatment to 
avoid metastatic disease. The minimal disease setting in which the disease can be monitored 
easily, with a treatment regimen that builds on established standards of care with an easily 
administered regimen, offers the highest probability of demonstrating clinical benefit in a short 
time frame. 
 
Our central hypothesis is that abiraterone-based treatments will be superior to conventional 
androgen depletion. To test our hypothesis we will evaluated three treatment groups: abiraterone 
acetate alone, abiraterone acetate plus degarelix, and degarelix alone. We have selected degarelix 
to avoid the initial serum testosterone elevations that occur with GnRH agonists/antagonists 
which are not completely blocked with the currently available anti-androgens.3,17 Degarelix 
treatment reduces serum androgen levels to a castrate range within 48 hours.18 
1.7 
Choice of Undetectable PSA as the Primary Endpoint 
Survival is recognized as a “gold standard” primary endpoint in clinical trials. As is the case for 
the treatment of the primary tumor, we postulate that disease eradication as evidenced by an 
undetectable PSA is a clinically meaningful therapeutic objective for men with a rising PSA and a 
PSADT ≤ 9 months without definitive metastatic disease. Patients with pelvic and/or 
retroperitoneal nodes < 2 cm in short axis will be permitted on study, as they are considered not to 
have definitive metastases. 
 
For men who are successfully treated surgically, the serum PSA level should decline to below 
detectable levels within 21 to 30 days based on its half-life.49,50 The reported level of detectable 
serum PSA by current commercial assays is 0.1 ng/mL (undetectable levels are expressed as <0.1 
ng/mL).49 Consequently, the most acceptable threshold for a detectable PSA after prostatectomy 
is 0.05 ng/mL, which is a measurable value above the level detectable by assay. In this trial all 
PSA assays will be performed at the location of participant registration using a routine PSA 
assay. 


19 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
2. 
OBJECTIVES 
2.1 
Primary Objective 
The objective of this protocol is to study abiraterone acetate, alone or in combination with 
degarelix, a GnRH antagonist, in men with non-castrate levels of testosterone and a rising PSA 
following radical prostatectomy without clinically metastatic disease to determine whether 
abiraterone acetate can potentially cure (primary endpoint: progression-free survival at 18 months 
from the time of treatment initiation) a proportion of men of this population. Men with pelvic 
and/or retroperitoneal nodes < 2 cm in short axis will be permitted on study, as they are 
considered not to have definitive metastases. 
 
2.2 
Secondary Objectives 
• To determine the PSA response rate. 
• To determine the effects of each arm on overall quality of life, with particular attention to 
libido, potency, anxiety, depression, hot flashes, and fatigue. 
• To determine the frequency and intensity of non-hematologic adverse events. 
• To determine testosterone and LH recovery rates. 
 
3. 
PATIENT SELECTION 
3.1 
Target Population 
Post-radical prostatectomy men with a serum testosterone of 150 ng/dL or greater who now have 
a rising PSA and a PSADT ≤ 9 months without metastatic disease. However, patients with pelvic 
and/or retroperitoneal nodes < 2 cm in short axis will be permitted on study, as they are 
considered not to have definitive metastases. 
 
3.2 
Inclusion Criteria 
To be included in this study, patients must meet all of the following criteria: 
 
• Willing and able to provide written informed consent and Authorization for Use and Release 
of Health and Research Study Information (HIPAA authorization) 
 
NOTE: HIPAA authorization may be either included in the informed consent or obtained 
separately. 
 
• Male aged 18 years and above 
 
• Patients must have undergone local treatment via radical prostatectomy 
 
o Patients who have received primary radiation therapy followed by a salvage 
radical prostatectomy are eligible. 
 
o Patients who have had post-operative radiation therapy for presumed locally 
recurrent disease are eligible 
• Histologically confirmed prostate cancer (per standards at Institution of participant 
registration) currently with progressive disease, defined as: 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
20 of 69 
 
 
o 
Rising PSA (50% or more increase to a level of 1 ng/mL or more, based on 
at least 3 PSA determinations obtained at least 1 week apart). The 50% rise in PSA is 
across the 3 determinations, and these determinations do not need to be sequential. 
 
AND 
 
o PSADT ≤ 9 months as calculated according to the Memorial Sloan-Kettering Cancer 
Center nomogram (http://www.mskcc.org/mskcc/html/10088.cfm) 
• Patients with pelvic and/or retroperitoneal nodes < 2 cm in short axis are eligible as they are 
not considered to have definitive metastases. 
 
• Patients must have a serum testosterone of 150 ng/dL or greater 
• ECOG performance status of ≤ 2 (Appendix A) 
 
• Adequate bone marrow, hepatic, and renal function, as evidenced within 14 days prior to 
treatment initiation by: 
o Absolute neutrophil count (ANC) ≥ 1500/mm3 
o Platelet count ≥ 100,000/mm3 
o Hemoglobin ≥ 9 g/dL without need for hematopoietic growth factor or transfusion 
support within 30 days prior to treatment initiation 
o Aspartate aminotransferase (AST) ≤ 1.5 times the upper limit of the normal range (x 
ULN) 
o Alanine aminotransferase (ALT) ≤ 1.5 x ULN 
o Total bilirubin ≤ 1.5 x ULN 
o Serum creatinine of ≤ 1.5 mg/dl or Calculated creatinine clearance of ≥ 60 mL/min 
o Serum albumin ≥ 3.0 g/dL 
o Serum potassium ≥ 3.5 mEq/L 
• At least 4 weeks and recovery to Grade 0‐1 from reversible effects of prior surgery (i.e., 
incisional pain, wound drainage) 
 
• Able to swallow the study drug whole as a tablet 
 
• Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least 
two hours before and for at least one hour after the dose of abiraterone acetate is taken 
 
• Patients who have partners of childbearing potential must be willing to use a method of birth 
control with adequate barrier protection as determined to be acceptable by the principal 
investigator during the study and for 1 week after last dose of abiraterone acetate. 
 
3.3 
Exclusion Criteria 
Patients that meet any of the criteria listed below will not be eligible for study entry: 
• Prior cytotoxic chemotherapy or biologic therapy for prostate cancer 
• More than 8 months of prior hormonal therapy (e.g., gonadotropin-releasing hormone analogs, 
megestrol acetate, or Casodex) 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
21 of 69 
 
 
Note: Patients who have been on prior hormonal therapy must wait at least 1 year 
after the drug is fully metabolized to start treatment on protocol. 
• Prior ketoconazole, abiraterone acetate, or enzalutamide for the treatment of prostate cancer. 
• Known brain metastasis or evidence of metastatic disease by CT scan, physical exam, or bone 
scan within 4 weeks of registration 
o Patients with equivocal uptake on a bone scan that in the clinician’s opinion do not 
definitively constitute metastatic disease are eligible 
• Currently active second malignancy, except non-melanoma skin cancer 
• Significant medical condition other than cancer, that would prevent consistent and compliant 
participation in the study that would, in the opinion of the investigator, make this protocol 
unreasonably hazardous including but not limited to: 
o Active infection or other medical condition that would make prednisone/prednisolone 
(corticosteroid) use contraindicated 
o Severe hepatic impairment (Child-Pugh Class C) 
o History of gastrointestinal disorders (medical disorders or extensive surgery) that 
may interfere with the absorption of the study agents 
o Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg); 
patients with a history of hypertension are allowed provided blood pressure is 
controlled by anti-hypertensive treatment 
o Active or symptomatic viral hepatitis or chronic liver disease 
o History of pituitary or adrenal dysfunction 
o Clinically significant heart disease as evidenced by myocardial infarction, or arterial 
thrombotic events in the past 6 months, severe or unstable angina, or New York 
Heart Association (NYHA) Class III or IV heart disease or cardiac ejection fraction 
measurement of < 50 % at baseline 
o Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy 
o Uncontrolled diabetes mellitus 
o Active psychiatric condition 
• Use of any prohibited concomitant medications (Section 5.5.2) within 30 days prior to Cycle 
1, Day 1 
• Pre-existing condition that warrants long-term corticosteroid use in excess of study dose 
• Grade > 2 treatment-related toxicity from prior therapy 
• Known allergies, hypersensitivity or intolerance to abiraterone acetate, prednisone or degarelix 
• Administration of an investigational therapeutic within 30 days of Cycle 1, Day1 
• Any condition which, in the opinion of the investigator, would preclude participation in this 
trial 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
22 of 69 
 
 
4. 
PATIENT REGISTRATION 
A centralized registration procedure will be used. After eligibility screening, patients who are 
selected to participate will be registered with the Lead Center (MSKCC). 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 or study activities. 
 
4.1 
Lead Center (MSKCC) Registration 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am 
– 5:30pm at 646-735-8000. Registrations must be submitted via PPR Electronic Registration 
System (http://ppr/). The completed signature page of the written consent/RA or verbal script/RA, 
a completed Eligibility Checklist and other relevant documents must be uploaded via the PPR 
Electronic Registration System. 
 
4.1.2 
For participating sites 
Central registration for this study will take place at Memorial Sloan Kettering Cancer 
Center (MSKCC) via Prostate Cancer Clinical Trials Consortium, LLC (PCCTC). 
 
To complete registration and enroll a participant from another institution, the study staff 
at that site must contact the designated research staff at PCCTC to notify him/her of the 
participant registration. The site staff then needs to  email registration/eligibility 
documents to the PCCTC via email at PCCTC@mskcc.org. 
 
The following documents must be sent for each enrollment within 24 hours of the 
informed consent form being signed: 
 
• The completed or partially completed MSKCC eligibility checklist 
• The signed informed consent and HIPAA Authorization form 
• Supporting source documentation for eligibility questions (laboratory results, 
pathology report, radiology reports, MD notes, physical exam sheets, medical history, 
prior treatment records, and EKG report). 
 
Upon receipt, the research staff at PCCTC will conduct an interim review of all 
documents. If the eligibility checklist is not complete or source documentation is missing, 
the patient will be registered PENDING and the site is responsible for sending completed 
registration documents within 30 days of the consent. 
 
If the eligibility checklist is complete, participant meets all criteria, all source documentation is 
received, the participating site IRB has been activated by MSKCC, and the site is in good 
standing with MSKCC, the PCCTC research staff will send the completed registration 
documents to the MSKCC Protocol Participant Registration (PPR) Office to be enrolled as 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
23 of 69 
 
 
stated in section 4.1. The participant will be registered. 
 
Once eligibility has been established and the participant is registered, the participant will 
be assigned an MSKCC Clinical Research Database (CRDB) number (protocol 
participant number). This number is unique to the participant and must be written on all 
data and correspondence for the participant. This protocol participant number will be 
relayed back to study staff at the registering site via e-mail and will serve as the 
enrollment confirmation. 
 
4.1.3 
Randomization 
Details regarding randomization are found in section 5.4. Staff at the registering site will 
receive the treatment plan for the randomized participants via email at the time they receive 
their participant ID. 
 
4.2 
Institutional Registration 
Patient registration at each study site/institution will be conducted according to the institution’s 
established policies. Patients must be registered with MSKCC and their local site/institution 
before beginning any treatment or study activities. 
 
4.2.1 
Informed consent 
Text regarding PCCTC should be added to all institutional informed consent documents 
and sections in the research authorization/HIPAA forms (e.g., “Prostate Cancer Clinical 
Trial Consortium, , New York, NY”). 
 
Authorized study personnel should fully explain the scope of the study (Section 6) to 
each patient before obtaining informed consent. Patients should be advised of any known 
risks inherent in the planned procedures, any alternative treatment options, their right to 
withdraw from the study at any time for any reason, and their right to privacy. 
 
When obtaining informed consent, study personnel should: 
First: Confirm that the patient has received the research authorization/HIPAA form. This 
must be reviewed before confirming eligibility and obtaining informed consent. 
 
Next: Confirm eligibility as defined in Sections 3.2 and 3.3 (Inclusion and Exclusion 
Criteria). 
 
5. 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Study Drug (Abiraterone acetate) 
Abiraterone acetate 250-mg tablets are oval, white to off-white and contain abiraterone 
acetate and compendial (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 in tableting). 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. 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
24 of 69 
 
 
5.1.2 
Degarelix 
Degarelix is supplied as a powder to be reconstituted with Sterile Water for Injection, 
USP. A starting dose of 240 mg given as two subcutaneous injections of 120 mg at a 
concentration of 40 mg/mL will be administered. The starting dose is followed by 
maintenance doses of 80 mg administered  per institutional guidelines at a concentration 
of 20 mg/mL every 28 days (± 3 days) 
 
5.1.3 
Prednisone 
Prednisone (5 mg tablets) will be prescribed to patients assigned abiraterone acetate to be 
taken orally once daily with food. If a subject has been receiving glucocorticoids other 
than prednisone or prednisolone, it will be necessary to switch the glucocorticoid to 
prednisone or prednisolone 5 mg once daily prior to Day 1. 
 
5.2 
Treatments Administered 
5.2.1 
Group 1: Abiraterone acetate and prednisone 
Patients randomized to abiraterone acetate and prednisone (Group 1) will be instructed to 
take 1000 mg (four 250 mg tablets) of abiraterone acetate orally (PO) at least 1 hour 
before a meal and 2 hours after a meal every day. These patients will also be treated with 
prednisone 5 mg once daily with food. 
 
5.2.2 
Group 2: Abiraterone acetate plus degarelix and prednisone 
Patients randomized to abiraterone acetate plus degarelix and prednisone (Group 2) will 
be instructed to take 1000 mg (four 250 mg tablets) of abiraterone acetate orally (PO) at 
least 1 hour before a meal and 2 hours after a meal every day and prednisone 5 mg once 
daily with food. Patients will also be given two subcutaneous injections of degarelix 120 
mg on Cycle 1, Day 1(starting dose) and 80 mg subcutaneous  doses (maintenance doses) 
every 28 days (±3 days) thereafter. 
 
5.2.3 
Group 3: Degarelix alone 
Patients randomized to degarelix alone (Group 3) will be given two subcutaneous 
injections of degarelix 120 mg on Cycle 1, Day 1 (starting dose) and 80 mg subcutaneous 
doses (maintenance doses) every 28 days (± 3 days) thereafter. 
 
5.3 
Selection and Timing of Dose for Each Patient 
Each treatment cycle consists of 28 consecutive days (4 weeks). Patients will take study treatment 
for 8 cycles (32 weeks) or until disease progression or patient withdrawal. The treatments are not 
blinded. The dose of prednisone will remain unchanged in the event that the study drug dose is 
changed. The dose of prednisone will only be changed at the discretion of the treating physician. 
Treatment with abiraterone acetate will be continuous from Day 1. If a dose is missed, the next 
dose should be given as planned without making up the missed dose. Degarelix will be 
administered approximately every 28 days. 
 
5.4 
Randomization 
Patients will be randomized after the investigator has verified that all eligibility criteria have been 
met and the patient is registered to the study. Patients will be randomized to receive abiraterone 
acetate and prednisone (Group 1), abiraterone acetate plus degarelix and prednisone (Group 2) or 
degarelix alone (Group 3) in a 1:1:1 ratio. 


25 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
5.5 
Concomitant Medications 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, over-the- 
counter medications, and alternative therapies must be documented. The principal investigator 
should be alerted if the patient is taking any prohibited agents. Concurrent enrollment in another 
therapeutic clinical investigation is prohibited. 
 
5.5.1 
Supportive care medications 
Supportive care medications are permitted with their use following institutional 
guidelines. 
 
The following supportive care medications are considered permissible during the study: 
• 
Conventional multivitamins, selenium and soy supplements 
• 
Additional systemic glucocorticoid administration such as “stress dose” 
glucocorticoid is permitted if clinically indicated for a life threatening medical 
condition, and in such cases, the use of steroids will be documented as concomitant 
drug 
 
5.5.2 
Prohibited within 30 days prior to administration of study treatment 
• 
Spironolactone 
• 
5 α–reductase inhibitors (e.g., finasteride, dutasteride) 
• 
Saw Palmetto 
• 
Use of other investigational drug therapy 
 
5.5.3 
Prohibited before enrollment and during administration of study treatment 
• Androgen Receptor Partial Agonists 
• Ketoconazole (Ketoconazole shampoo or topical cream/ointment for treatment of a 
past fungal infection does not exclude patients) 
• Previous abiraterone acetate or other investigational CYP17 inhibitors (e.g., TAK- 
700) 
• Chemotherapy (e.g., docetaxel, mitoxantrone, vinorelbine) 
• Immunotherapy (e.g., cancer vaccines, GM-CSF) 
• Estrogens 
• PC-SPES or PC-HOPE herb mixtures Radiopharmaceuticals (e.g., 89Sr, 153Sm, 
Fludrocortisone acetate) 
 
5.5.4 Prohibited during administration of study treatment 
• 
Antiandrogens 
o Non-steroidal antiandrogens (e.g., bicalutamide, flutamide, nilutamide) 
o Steroidal antiandrogens (e.g., megestrol acetate, cyproterone) 
 
5.5.5 The following medications are not excluded or prohibited, but are strongly discouraged: 


26 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
• 
Digoxin; hypokalemia which is an expected adverse effect of abiraterone 
may enhance digoxin toxicity. Investigators are encouraged to consider whether 
patients needing digoxin could be managed with a different drug. 
• 
Pomegranate juice/supplements; pomegranate juice has been associated with 
stabilization of PSA in a phase II study. 
• 
Indole-3-carbinol; indole-3-carbinol has been suggested to have estrogenic effects, 
which theoretically could affect prostate cancer. However, no clinical trial results in 
men with prostate cancer are available. 
 
• 
Flaxseed Oil; flaxseed oil has been associated with having estrogenic and 
antiestrogenic effects and can potentially lower potassium level. Flaxseed oil may 
theoretically lead to progression of some forms of cancer, including prostate cancer. 
However, no clinical trial results in men with prostate cancer are available. 
 
5.5.6 
Potential for drug-drug interactions 
Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme 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 concomitantly with abiraterone acetate. 
 
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 
acetate 
 
 
5.6 
Packaging and Labeling 
Abiraterone acetate tablets will be provided to each site packaged for patient assignment at the 
time of randomization. Patients will be provided with a 30-day supply to allow for visits to occur 
every 28 days with a ± 3 day window. Information presented on the labels for investigational 
product will comply with applicable local regulations. Site pharmacist or medically qualified staff 
will dispense the study treatment to each patient in accordance with this protocol. 


27 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
Degarelix will be prescribed from open pharmacy stock. 
 
Prednisone will be prescribed by the treating physician. 
 
5.7 
Storage and Accountability 
5.7.1 
Storage requirements 
Store at 20oC to 25oC (68oF to 77oF); excursions permitted to 15oC to 30oC (59oF to 
86°F). 
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. 
Study staff and caregivers should be notified of this information, to ensure the appropriate 
precautions are taken. 
 
5.7.2 
Drug dispensing log and pill diary 
Study site personnel will record all study drugs administered during this trial on the drug- 
dispensing log. 
The drug dispensing log will contain the following information: 
• patient initials and study identification number 
• date(s) of study drug dispensed 
• quantity of study drug dispensed 
• drug lot number 
• expiration date (if known) 
• initials of dispensing pharmacist 
Subjects will be provided with a diary in which to record their intake of study drug. 
However, the actual number of tablets taken by the subject must be calculated from the 
number of tablets dispensed and returned. 
 
5.8 
Criteria for Discontinuation of Study Treatment 
In the absence of treatment delays because of adverse events, treatment will continue for 8 
months until one of the following criteria applies: 
• Patient decides to withdraw from the study 
• PSA progression determined as follows: 
PSA is assessed every 28 days (± 3 days) using a routine PSA assay. If a measured PSA is 
higher than the preceding value, then the rising PSA will be confirmed in 4 weeks (±  3 days). 
If that third PSA value is higher still and the range of values is 50% above the baseline, then 
the patient is off study treatment. If not, the patient will remain on study, and the PSA will 
once again be checked when the patient presents for his monthly clinic visit. 
• Radiographic progression (in the opinion of the investigator) 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) that may or may not be directly related to treatment but that, in 
the judgment of the treating physician, makes it dangerous for the patient to be retreated 


28 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
• 
General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment, in the judgment of the investigator 
• Initiation of non-study therapy for metastatic prostate cancer 
Because an excessive rate of withdrawals can render the study uninterruptable, unnecessary 
withdrawal of patients should be avoided. When a patient discontinues treatment early, the 
investigator should make every effort to contact the patient and to perform a final evaluation. The 
reason(s) for withdrawal should be recorded. 
When protocol therapy is discontinued based on subject or investigator decision and the subject 
has not withdrawn consent, that subject will be followed for adverse events (AEs) for 30 days 
after the last dose of study medication. In the event that a serious adverse event (SAE) regardless 
of causality is ongoing or newly reported 30 days after the last dose of study medication, the 
subject will be followed until resolution of the event. 
 
5.9 
Criteria for Discontinuation of Post-Treatment Follow-Up 
All patients who complete 8 months of protocol therapy will be followed for 10 additional 
months until one of the following criteria applies: 
• Patient decides to withdraw from the study 
• PSA progression determined as  detectable PSA per the assay at the institution of registration 
and confirmed by consecutive observation at the next scheduled visit. 
• Radiographic progression (in the opinion of the investigator) 
• Initiation of non-study therapy for metastatic prostate cancer 
 
 
6. 
STUDY PROCEDURES 
The following assessments and procedures will occur during the study. A schedule of assessments 
is provided in Table 4. 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
29 of 69 
 
 
Table 4  Study Calendar 
Screening 
Treatment Period (8 cycles) 
Post-treatment 
Follow-up 
(Every 28 days ±7 
days for 10 months) 
Within 30 days 
prior to 
protocol 
therapy 
initiation 
Within 14 days 
prior to 
protocol 
therapy 
initiation 
Day 1 of each 28 
day cycle (+ 3 
days) 
Day 15 (+ 2 days) of 
cycles 1,2,3 
[Abiraterone 
treatment arms only] 
End of Treatment2 
Informed consent and research authorization 
X 
Demographics, medical history 
X 
Interim medical history 
X 
X 
X 
X 
Physical examination3 
X 
X 
X 
X 
Histologic and radiographic confirmation of 
disease 
X 
ECOG or Karnofsky performance status 
X 
X 
X 
X 
CT of the chest, abdomen, and pelvis 
X 
X8 
X3,8 
Radionuclide bone scan 
X 
X8 
X3,8 
12-lead ECG 
X 
ECHO or MUGA 
X 
Laboratory tests4,7 
X 
X 
X7 
X 
X 
PSA 
X 
X 
X 
X 
Serum testosterone and LH 
X 
X 
X 
PRO assessments 
X 
X 
X 
X 
Correlative studies (optional)8 
X 
Toxicity/AE assessment9 
X -------------------------------------------------------------------------------------------------------------------------------- X 
Concomitant medications 
X -------------------------------------------------------------------------------------------------------------------------------- X 
Abiraterone acetate + Prednisone (Arms 1 & 
2)6 
Daily x 8 months 
Degarelix injection (Arms 2 & 3)6 
Monthly x 8 
months 
Abbreviations: CT, computerized tomography; ECG, electrocardiogram; ECOG, Eastern Cooperative Group; LH, luteinizing hormone; MRI, magnetic resonance imaging; 
MUGA, multiple gated acquisition; PRO, patient-reported outcome 
1. Physical examination includes vital signs. Weight will be recorded at every visit. Height will be recorded at screening visit only. Vital signs include upright blood pressure, 
heart rate, respiratory rate, and oral or aural body temperature. 
2. End of treatment visit will take place 28 ± 3 days after Cycle 8 day one, or within 7 days of last dose of study drug for those who discontinue treatment prematurely. 
3. Post-treatment imaging conducted at post-treatment follow-up 10 (±14 days), or if patient discontinues follow-up for reasons described in Section 5.9 
4. Laboratory tests are outlined in Section 6.5.1 
5. Prostate tissue samples will be collected for those patients who give their consent (Section 6.10) 
6. Daily abiraterone acetate administered with once daily prednisone. Details on all treatments administered are outlined in Section 5.2 
7. Liver function tests (AST, ALT and total bilirubin) should be performed on Day 15 (±2 days) of the first three cycles. 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
39 of 69 
 
 
 
8. If patients have had scans within 30 days of their visit, scans do not need to be repeated. 
9. AEs will be assessed and recorded after informed consent is obtained through 30 days of last dose, or the event resolves, stabilizes, returns to baseline condition or is attributed 
to agents other than study product, or to factors unrelated to study conduct, whichever occurs first 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
Informed Consent 
6.1 
31 of 69 
12-187 A(15) Protocol.DOCX 
 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB-approved consent form indicating their 
consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
• The nature and objectives, potential risks and benefits of the intended study. 
• The length of study and the likely follow-up required. 
• Alternatives to the proposed study. This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies. 
• The name of the investigators responsible for the protocol. 
• The right of the participant to accept or refuse study interventions/interactions and to withdraw 
from participation at any time. 
• Text regarding the PCCTC should be added to all institutional informed consent documents 
and sections in the research authorization/HIPAA forms (e.g., “Prostate Cancer Clinical Trial 
Consortium”) 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
6.2 
Medical History 
Medical history, such as previous treatments, procedures, and conditions will be collected during 
the screening period. 
 
6.3 
Physical Examination 
Evaluations should be performed by the same evaluator throughout the study whenever possible. 
Weight will be recorded at every visit. Height will be recorded at screening visit only. 
Vital signs include upright blood pressure, heart rate, respiratory rate, and oral or aural body 
temperature. 
 
6.4 
Cardiac Function 
To assess cardiac function at baseline, a 12-lead ECG and a Multiple Gated Acquisition (MUGA) 
scan should be obtained. Echocardiography can be used if MUGA is not available or when 
echocardiography is standard of care at the study site. Baseline measurement of left ventricular 
ejection fraction (LVEF) will be performed. Control hypertension and correct hypokalemia before 
treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least 
monthly during active treatment. 


32 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
Clinical laboratory Tests 
6.5 
 
 
 
6.5.1 
Laboratory parameters 
Clinical laboratory tests will include the following (Table 5): 
 
Table 5. List of laboratory tests 
 
Hematology: 
 
- Hematocrit (Hct) 
 
- Hemoglobin (Hgb) 
 
- Platelet count 
 
- Red blood cell (RBC) count 
 
- White blood cell (WBC) count with 
differential 
 
Serum Chemistry: 
- Alkaline phosphatase (ALK-P) 
- Alanine aminotransferase (ALT; SGPT) 
- Aspartate aminotransferase (AST; SGOT) 
- Blood urea nitrogen (BUN) 
- Carbon dioxide (CO2) 
- Chloride (Cl) 
- Creatinine (Cr) 
- Glucose (Glu) 
- Lactate Dehydrogenase (LDH) 
- Potassium (K) 
- Sodium (Na) 
- Total bilirubin 
- Calcium (Ca) 
- Albumin (Alb) 
 
 
 
6.5.2 
Sample collection, storage and shipping 
Local laboratories will analyze all hematology, blood chemistry collected for the study. 
Samples will be analyzed at a facility meeting Clinical Laboratory Improvement 
Amendments (CLIA) requirements and/or using methods documented in a methods 
validation report. 
 
6.6 
Efficacy/Response Assessments 
PSA will be assessed every 28 days (± 3 days) using a routine PSA assay. 
 
6.6.1 
Primary efficacy endpoint 
Progression-free survival (PFS) defined as achieving and maintaining an undetectable 
PSA level (per institution of registration) with a non-castrate level of testosterone (>150 
ng/dL) will be assessed at 18 months from the start of randomization (PSA0). 
 
6.6.2 
Secondary response endpoint 
Treatment response defined as achieving and maintaining an undetectable PSA level (per 
institution of registration) with a non-castrate level of testosterone (>150 ng/dL) will be 
assessed at 8 months from PSA0. 
 
6.7 
Testosterone and Luteinizing Hormone Recovery Rates 
Serum testosterone and LH recovery rates will be measured at 8 months from the start of 
treatment and at each month of the 10 month follow up period (secondary endpoint measure). 
 
6.8 
Patient-reported Outcomes 
Effects of each arm on health-related quality of life will be assessed via PRO Survey (Appendix 
B) completed on paper by the patient at the following study visits: Screening, each Day 1 of 
Treatment Cycle, End of Treatment, and each Post-Treatment Follow-up.  The following adverse 
symptom events will be assessed by 15 items from the NCI PRO-CTCAE: libido, potency, 
anxiety, depression, hot flashes, fatigue, joint swelling, muscle discomfort, diarrhea, and cough. 
Quality of life will also be assessed by the Linear Analog Scale Assessment (LASA) single item 


33 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
measure of overall quality of life.51 This item has been shown to be more responsive than multi- 
 
 
item measures and to cause less patient burden, and is used across NCI cooperative group trials, 
particularly in the NCCTG, ACOSOG, and CALGB. All items in the PRO Survey employ a 7- 
day recall period. The PRO Survey contains a total of 16 items and will take 5-8 minutes to 
complete. 
 
6.9 
Safety Evaluation 
Frequency and intensity of non-hematologic adverse events will be recorded (secondary 
endpoint measure) per Section 9.2. 
 
6.10 
Correlative Studies 
Baseline tumor tissue will be collected for those patients who give their consent for correlative 
analyses and pharmacogenomic studies. Tissue blocks (preferred) or unstained slides known to 
contain cancer should be obtained on primary tumors from patients. Tumor tissue from the radical 
prostatectomy is preferred; however, if it is unavailable, tumor from a diagnostic prostate biopsy 
is acceptable. All samples will be processed at MSKCC.  Sample shipment to the central 
laboratory (MSKCC) may occur any time during the study. 
 
Tissue samples will be utilized for morphologic assessment, percent tumor involvement (if 
applicable), and immunohistochemistry. The immunohistochemical markers assessed may be AR, 
PTEN, PSMA, fatty acid synthase (FASN), phospho-AMPK, phospho-ACC, phospho-S6 kinase, 
phospho-Akt for the assessment of the AMPK, lipid synthesis, mTOR pathways, and 
immunological markers. 
 
Gene expression profiling may be performed from residual samples by utilizing various 
technologies (e.g. qRT-PCR, NanoString DASL assay). Tissue or purified DNA and RNA from 
these samples may also be examined to detect genomic abnormalities (somatic mutations, 
deletions, amplifications) in selected genes by various methods (e.g. FISH, sequencing, 
microarrays). 
 
A Central Laboratory will analyze all tissue samples collected for the study. Samples will be 
analyzed at a facility meeting regulatory requirements and/or using methods documented in a 
methods validation report. 
 
6.10.1 Additional research 
MSKCC and PI shall not conduct any research on biological samples which is not 
required by the protocol for the conduct of the study at or by MSKCC and at each site 
during the study. 
 
6.10.2 Storage, handling and disposal 
PCCTC and PI shall ensure biological samples being analyzed in the study at each site 
are handled, stored and disposed of at the end of the study in accordance with the terms 
of the applicable consents and permissions for each donor and in accordance with all 
applicable laws. 
 
7. 
STUDY ACTIVITIES 
7.1 
Within 30 Days Prior to Protocol Therapy Initiation 
Before initiating any screening activities, the scope of the study should be explained to each 
patient. Patients should be advised of any known risks inherent in the planned procedures, any 
alternative treatment options, their right to withdraw from the study at any time for any reason, 
and their right to privacy. After this explanation, patients should be asked to sign and date a 


34 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
research authorization/HIPAA form and an IRB-approved statement of informed consent that 
 
 
meets the requirements of the Code of Federal Regulations (Federal Register Vol. 46, No. 17, 
January 27, 1981, part 50) 
The screening visit will determine patient eligibility according to the inclusion and exclusion 
criteria (Sections 3.2 and 3.3). The following assessments will be performed at this visit: 
• Obtain informed consent and research authorization 
• Record demographics (including age) and medical history (including prior treatment 
for prostate carcinoma and PSA kinetics) 
• Interim medical history 
• Conduct physical exam (vital signs, height/weight, etc.) 
• Obtain histologic and radiographic confirmation of disease 
• Blood samples for serum testosterone and LH levels 
• Assess ECOG performance status (Appendix A) 
• PRO Survey (Appendix B) 
• CT of the chest, abdomen, and pelvis 
• Radionuclide bone scan 
• ECG 
• MUGA or ECHO 
• Discuss concurrent medications (see Section 5.5 for a listing of medications with the 
potential for drug interactions) 
• Collection of prostate tissue for correlative studies (optional; see Section 6.10). 
Note: Tissue blocks (preferred) or unstained slides known to contain cancer should be 
obtained on primary tumors from patients. Tumor tissue from the radical 
prostatectomy is preferred; however, if it is unavailable, tumor from a diagnostic 
prostate biopsy is acceptable. Sample shipment to the central laboratory may occur 
any time during the study. 
Relevant information should be documented. The institutional registration should be finalized, 
and appropriate documents (i.e., signed informed consent, research authorization/HIPAA form, 
and supporting source documentation for eligibility questions) faxed or emailed to the lead site. 
 
7.2 
Within 14 Days Prior to Protocol Therapy Initiation 
A visit within 14 days prior to initiation of protocol therapy will further determine patient 
eligibility and collect baseline patient data. The visit must include the assessments listed below: 
• Blood samples for laboratory tests (Section 6.5) and PSA 
 
7.3 
Treatment Period (Day 1 ±3 days to Week 32 ± 3 days) 
Patients will receive study treatment for up to eight 28-day treatment cycles or less if one of the 
following occurs: disease progression, unacceptable toxicity, death, patient refusal or treatment 
delay beyond the time frame that is permitted for each treatment (See Section 5.8). All 
assessments must take place before scheduled degarelix injection (Group 2 and Group 3). 


35 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
7.3.1 
Day 1(± 3 days) 
 
 
On Day 1 of every 28-day cycle the following study activities will occur while a patient 
is continuing on protocol therapy: 
• Interim medical history 
• Physical exam 
• Assess ECOG performance status (Appendix A) 
• PRO Survey (Appendix B) 
• Toxicity/AE assessment 
• Degarelix injection (Group 2 and Group 3) 
• Blood samples for laboratory tests (Section 6.5) and PSA 
• Discuss concurrent medications (see Section 5.5 for a listing of medications with the 
potential for drug interactions) 
7.3.2 
Day 15(± 2 days) – For patients in the Abiraterone acetate treatment arms only 
On Day 15 of cycles 1, 2 and 3 the following study activities will occur while a patient is 
continuing on protocol therapy: 
 
• Liver function laboratory tests (AST, ALT and total bilirubin) 
 
7.3.3 
End-of-treatment 
28 ± 3 days after Cycle 8 Day 1 visit, or within 7 days of last dose for those who 
discontinue protocol treatment prematurely. 
• Interim medical history 
 
• Physical exam 
• Assess ECOG performance status (Appendix A) 
• PRO Survey (Appendix B) 
• Toxicity/AE assessment 
• Blood samples for laboratory tests (Section 6.5) and PSA 
• Discuss concurrent medications (see Section 5.5 for a listing of medications with the 
potential for drug interactions) 
 
• Blood samples for serum testosterone and LH levels 
 
• CT of the chest, abdomen, and pelvis 
 
Radionuclide bone scanPatients withdrawn from the study because of AEs do not need 
blood samples for serum testosterone and LH levels, CT of the chest, abdomen and 
pelvis, or a radionuclide bone scan at their End-of-treatment visits. 


36 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
7.4 
Post-treatment Follow-up 
Patients completing 8 cycles of protocol therapy, in the absence of documented disease 
progression or initiation of non-study therapy for metastatic prostate cancer, will be seen every 28 
days (± 7 days) for up to 10 months from the date of their End of Treatment visit. The following 
assessments will be completed at each post-treatment follow-up visit: 
• Interim medical history 
• Physical exam 
• Assess ECOG performance status (Appendix A) 
• PRO Survey (Appendix B) 
• Toxicity/AE assessment 
• Blood samples for laboratory tests (Section 6.5) and PSA 
• Discuss concurrent medications 
• Blood samples for serum testosterone and LH levels 
• CT of the chest, abdomen, and pelvis (Follow-up 10 only, or for patients who discontinue 
follow-up due to reasons described in section 5.9) 
• Radionuclide bone scan (Follow-up 10 only, or for patients who discontinue follow-up due to 
reasons described in section 5.9) 
 
 
Patients who have discontinued protocol treatment due to AEs will be followed until the adverse 
event has either resolved or stabilized. Reasons for premature withdrawal should be determined 
and noted. 
 
8. 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the medicinal 
product. 
 
8.1.2 
Adverse Events of Special Interest 
Please refer to Prescribing Information Packet for all relevant safety information. 
 
8.1.3 
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. 


37 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
8.1.4 
J&J Medicinal Product 
The specific J&J drug under study and any other J&J medicinal product. 
 
8.1.5 
Product Quality Complaint (PQC) 
Any discrete concern that questions the identity, quality, durability, reliability, safety, 
efficacy or intended performance of a drug product. 
 
A complaint may allege an injury or malfunction associated with the use of the drug 
product. It may also involve the design, literature, packaging, advertising, availability, 
physical appearance or promotion of the drug product. 
 
8.1.6 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered ‘‘serious’’ if it results in 
any of the following outcomes: 
• Death, 
• A life-threatening adverse event, 
o An adverse event or suspected adverse reaction is considered ‘‘life-threatening’’ if 
its occurrence places the patient or subject at immediate risk of death. It does not 
include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
• A congenital anomaly/birth defect, 
• Is a suspected transmission of infectious agents by a medicinal product 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.1.7 
Special Reporting Situations 
When a report contains a J&J product, an identifiable patient, and identifiable reporter, 
the following events represent Special Reporting Situations: 
 
• Overdose of a Johnson & Johnson medicinal product 
• Pregnancy exposure (maternal and paternal) 
• Exposure to a medicinal product from breastfeeding 
• Suspected abuse/misuse of a medicinal Johnson & Johnson product 
• Inadvertent or accidental exposure to a medicinal Johnson & Johnson  product 
• Any failure of expected pharmacological action (i.e., lack of effect) of a Johnson & 
Johnson medicinal product 


38 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
• 
Unexpected therapeutic or clinical benefit from use of a Johnson & Johnson 
medicinal product 
• Medication error involving a Johnson & Johnson product (with or without patient 
exposure to the medicinal Johnson & Johnson product, e.g., name confusion) 
• Suspected transmission of any infectious agent via a medicinal product. 
 
8.2 
Management of Adverse Events, Serious Adverse Events and Special Reporting Situations 
For each subject, AEs, SAEs, and Special Reporting Situations should be recorded after informed 
consent is obtained until the subject has completed participation in the study as follows: 
An SAE or Special Reporting Situation must be reported if it occurs during a subject’s participation in 
the Study (whether receiving Study Product or not) and within 30 days of receiving the last dose of 
Study Product. 
Any serious adverse event or Special Reporting Situations that is ongoing when a subject completes 
his/her participation in the Study must be followed until any of the following occurs: 
• the event resolves or stabilizes; 
• the event returns to baseline condition or value (if a baseline value is available); 
• the event can be attributed to agents(s) other than the Study Product, or to factors unrelated to 
Study conduct. 
 
8.3 
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. Only abnormal laboratory values that are deemed clinically significant by 
the treating investigator are considered adverse events should be graded and attributed accordingly 
(per section 8.4). 
 
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 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 


39 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
test or finding should be recorded as an adverse event, using appropriate medical terminology 
(e.g., thrombocytopenia, peripheral edema, QT prolongation). 
 
8.4 
Grading Adverse Events 
8.4.1 
Grading severity 
All adverse events will be graded for intensity on a scale of 0 to 5. Severity grades will be 
recorded and based on the CTCAE v4.0. 
 
8.4.2 
Attributing causality 
After grading for severity, the investigator must evaluate all clinical AEs and clinically 
significant abnormal laboratory values for possible causal relationship to abiraterone 
acetate or degarelix. Causality attribution will be decided using the criteria outlined in 
Table 6. 
Table 6. Relationship of adverse event to study drug 
 
Relationship 
Description 
Unrelated 
AE is clearly not related to study drug 
Unlikely 
AE is doubtfully related to study drug 
Possible 
AE may be related to study drug 
Probable 
AE is likely related to study drug 
Definite 
AE is clearly related to study drug 
 
Abnormal laboratory values of clinical significance that were present at baseline and did 
not change in severity or frequency during experimental therapy or intervention and those 
that can obviously be attributed to underlying disease will be recorded as unrelated. 
 
8.5 
Reporting Adverse Events 
8.5.1 
Reporting serious adverse events 
All SAEs, events determined to be medically significant by the treating Investigator, 
and unknown reactions or unexpected events should be reported to MSKCC 
Principal Investigator and PCCTC within 24 hours of knowledge of the event using 
the contact information below. The initial report should include the following 
information at a minimum: 
• 
Protocol # and title 
• 
Study identification number, sex, age at time of event 
• 
Date the event occurred 
• 
Description of the SAE 
• 
Causal relationship to the study drug 
The PCCTC SAE Report Form (Appendix D) will be used by sites to report each SAE 
and should be submitted to the PCCTC within 3 calendar days of learning of the 
event. When a life-threatening event or death is unforeseen and indicates 
participants or others are at increased risk of harm, participating sites should notify 
PCCTC as soon as possible but within 24 hours of the time the participating site 
becomes aware of the event. Severity, causality, action taken, concomitant 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
40 of 69 
12-187 A(15) Protocol.DOCX 
 
 
medications, outcome, etc should be reported to the PCCTC as soon as possible. 
Participating sites are responsible for reporting all SAEs to their local IRB per local 
guidelines. Local IRB SAE approvals/acknowledgments must be sent to PCCTC upon 
receipt. 
The PCCTC will facilitate all SAE reporting to the MSK IRB/PB and Janssen Scientific 
Affairs, LLC within 24 hours of PCCTC awareness or identification of the event using 
the Janssen SAE Report Form (Appendix C). PCCTC is responsible for informing all 
participating sites about all unexpected SAEs that are either possibly, probably, or 
definitely related to the study intervention within 15 days of receiving the stamped 
SAE report from the MSK IRB/PB. PCCTC is responsible for informing all 
participating sites within 24 hours or on the next business day about a life- 
threatening event or death that is unforeseen and indicates participants or others 
are at increased risk of harm. 
Follow-up of adverse events should continue until the event and any sequela resolve 
or stabilize at a level acceptable to the investigator. 
SAE contact information for the MSKCC PI and PCCTC is listed below: 
Lead Site Study PI 
Howard Scher, MD 
Memorial Sloan Kettering Cancer Center 
Genitourinary Oncology Service 
1275 York Avenue 
New York, NY 10065 
scherh@mskcc.org 
 
PCCTC: 
Prostate Cancer Clinical Trials Consortium 
Phone: 646-888-0434/646-422-4383 
Email: PCCTC@mskcc.org 
 
8.5.2 
Reporting serious adverse events to Janssen Scientific Affairs, LLC 
Information regarding SAEs, AEs of Special Interest, Special Reporting Situations and 
PQCs will be transmitted to Janssen Scientific Affairs, LLC using their Serious Adverse 
Event Form (Appendix C), which must be completed and signed by a member of the 
investigational team within 24 hours of becoming aware of the event. PCCTC will 
facilitate all submissions to Janssen Scientific Affairs, LLC. 
 
The following methods are acceptable for transmission of safety information to the 
COMPANY: 
 
• 
Electronically vis Janssen SECURE email service at IIS-BIO-VIRO-  
GCO@its.jnj.com, or 
• 
For business purposes if SECURE email is non-functional; 
o Facsimile (fax) at 1-866-451-0371, of receipt of which is evidenced in a 
successful fax transmission report 
 
8.5.3 
Safety Reports 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
41 of 69 
12-187 A(15) Protocol.DOCX 
 
 
PCCTC will distribute outside safety reports from Janssen Scientific Affairs, LLC to the 
participating sites immediately upon receipt. Participating sites are responsible for 
submitting safety reports to their local IRB/PB as per their local IRB guidelines. All local 
IRB approvals/acknowledgments of safety reports must be sent to PCCTC upon receipt. 
 
 
8.5.4 
Unanticipated Problems 
Unanticipated problems involving risks to participants or others (UPs) are defined 
as any incident, experience or outcome that meets all of the following criteria: 
 
• 
Unanticipated (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; and 
 
• 
Related or possibly related to participating in the research (possibly related 
means there is a reasonable probability that the incident, experience or 
outcome may have been caused by procedures involved in the research); 
and 
• 
Suggests that the research place participants or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Participating sites are responsible for reporting all UPs to PCCTC as soon as possible 
but within 3 calendar days of learning of the event. UPs that are SAEs should be 
reported to PCCTC via SAE Report form as per Appendix D. All other UPs should be 
reported to PCCTC in a memo signed by the site PI. 
 
PCCTC is responsible for submitting UPs to the MSK IRB/PB according to 
institutional guidelines. In addition, PCCTC is responsible for notifying participating 
sites of all non-SAE UPs that may affect the sites. 
 
8.6 
Dose Modifications Procedure for Adverse Event Management 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Table 4. The 
NCI CTCAE v4.0 will be used to grade AEs. 
At each study visit for the duration of their participation in the study, patients will be evaluated 
for AEs (all grades), SAEs, and AEs that require study drug interruption or discontinuation. 
Patients discontinued from the treatment phase of the study for any reason will be evaluated 
approximately 30 days after the last dose of the study drug. 
The most common adverse reactions (≥ 5%) related to abiraterone acetate are joint swelling or 
discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, 
cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, factures and upper 
respiratory tract infection [see Adverse reactions (1.4.3)] 
 
Following prolonged therapy with corticosteroids, subjects may develop Cushing’s syndrome 
characterized by central adiposity, thin skin, easy bruising, and proximal myopathy. Withdrawal 
of the corticosteroid may result in symptoms that include fever, myalgia, fatigue, arthralgia, and 
malaise. This may occur even without other evidence of adrenal insufficiency. 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
42 of 69 
12-187 A(15) Protocol.DOCX 
 
 
8.6.1 
Management of hypokalemia 
Subjects who experience hypokalemia are to be managed as presented in Table 7. 
 
Table 7. Hypokalemia management 
Serum K+ 
Grade 
Action 
Further Action or Maintenance 
Low K+ or history 
of hypokalemia 
Weekly (or more frequent) 
laboratory electrolyte evaluations. 
Titrate dose to maintain a serum 
K+ ≥3.5 mM ≤5.0 mM (maintenance 
of subjects at ≥4.0 mM is 
recommended) 
<3.5 mM – 3.0 mM 
1 
Initiate oral or i.v. K+ 
supplementation. Consider 
monitoring magnesium and 
replacement if needed. 
Titrate dose to maintain a serum 
K+ >3.5 mM ≤5.0 mM (maintenance 
of subjects at ≥4.0 mM is 
recommended) 
<3.0 mM – 2.5 mM 
3 
Withhold abiraterone acetate 
(study) treatment and initiate oral 
or i.v. K+ and cardiac monitoring. 
Consider monitoring magnesium 
and replacement if needed 
Titrate dose to maintain a serum 
K+ >3.5 mM ≤5.0 mM (maintenance 
of subjects at ≥4.0 mM is 
recommended) 
<2.5 mM 
4 
Withhold abiraterone acetate 
(study) treatment and initiate oral 
or i.v. K+ and cardiac monitoring. 
Consider monitoring magnesium 
and replacement if needed. 
Off study 
 
8.6.2 
Management of hypertension 
• If Grade 1 or 2 adverse events occur, management per investigator. No study 
medication dose reduction. 
• If Grade 3 or 4 adverse events occur, hold study medication. Adjust or add 
medications to mitigate the toxicity or consider the specific mineralocorticoid receptor 
blocker, eplerenone. When hypertension resolves to ≤Grade 1, resume study 
medication at full dose. 
• If toxicity recurs, hold study medication, and adjust or add medications to mitigate the 
toxicity. When resolved to ≤Grade 1, resume study medication with the first dose level 
reduction (3 tablets, 750 mg of study medication). 
• If toxicity recurs, hold study medication, and adjust or add medications to mitigate the 
toxicity. When resolved to ≤Grade 1, resume study medication with the second dose 
level reduction (2 tablets, 500 mg of study medication). 
• If toxicity recurs despite optimal medical management and 2 dose level reductions, 
discontinue study medication. 
 
8.6.3 
Management of edema, fluid retention 
• If pedal edema occurs, supportive management per investigator. No study medication 
dose reduction. 
• If anasarca or pulmonary edema requiring supplemental oxygen occurs, hold study 
medication. Adjust or add medications to mitigate the toxicity and consider the 
specific mineralocorticoid receptor blocker, eplerenone. When toxicity resolves to 
≤Grade 1, resume study medication at full dose. 
• If toxicity recurs, hold study medication, and adjust or add medications to mitigate the 
toxicity. When resolved to ≤Grade 1, resume study medication with the first dose level 
reduction (3 tablets, 750 mg of study medication). 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
43 of 69 
12-187 A(15) Protocol.DOCX 
 
 
• 
If toxicity recurs, hold study medication, and adjust or add medications to 
mitigate the toxicity. When resolved to ≤Grade 1, resume study medication with the 
second dose level reduction (2 tablets, 500 mg of study medication). 
• If toxicity recurs despite optimal medical management and 2 dose level reductions, 
discontinue study medication 
 
8.6.4 
Management of hepatic impairment 
In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the 
recommended dose of abiraterone acetate to 250 mg once daily. A once daily dose of 250 
mg in patients with moderate hepatic impairment is predicted to result in an area under 
the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic 
function receiving 1,000 mg once daily. However, there are no clinical data at the dose of 
250 mg once daily in patients with moderate hepatic impairment and caution is advised. 
In patients with moderate hepatic impairment monitor ALT, AST, and bilirubin prior to 
the start of treatment, every week for the first month, every two weeks for the following 
two months of treatment and monthly thereafter. If elevations in ALT and/or AST greater 
than 5X upper limit of normal (ULN) or total bilirubin greater than 3X ULN occur in 
patients with baseline moderate hepatic impairment, discontinue abiraterone acetate and 
do not re-treat patients with abiraterone acetate. 
 
8.6.5 
Management of hepatotoxicity 
For patients who develop hepatotoxicity during treatment with abiraterone acetate (ALT 
and/or AST greater than 5X ULN or total bilirubin greater than 3X ULN), interrupt 
treatment with abiraterone acetate [see Warnings and Precautions (1.4.2)]. Treatment 
may be restarted at a reduced dose of 750 mg once daily following return of liver  
function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN 
and total bilirubin less than or equal to 1.5X ULN. For patients who resume treatment, 
monitor serum transaminases and bilirubin at a minimum of every two weeks for three 
months and monthly thereafter. 
 
If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be restarted at 
a reduced dose of 500 mg once daily following return of liver function tests to the 
patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin 
less than or equal to 1.5X ULN. 
 
If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment 
with abiraterone acetate. The safety of abiraterone acetate re-treatment of patients who 
develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or 
equal to 10X ULN is unknown. 
 
8.6.6 
Management of other non-mineralocorticoid based side effects 
• If Grade 1-2 toxicities occur, give supportive care per institutional guidelines. No 
study medication dose reduction. 
• If Grade 3 or higher toxicities occur, including headache (interferes with activities of 
daily living), nausea (total parenteral nutrition/intravenous fluids), vomiting (6 or 
more episodes in 24 hours, total parenteral nutrition/intravenous fluids), diarrhea 
(intravenous fluids, hospitalization, hemodynamic collapse), or any other toxicity 
judged related to study treatment is observed where the subjects safety is jeopardized, 
hold study medication. 
• When toxicity resolves to ≤ Grade 1, resume study medication at full dose. 


44 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
• 
If toxicity recurs, hold study medication, and adjust or add medications to 
mitigate the toxicity. When resolved to ≤ Grade 1, resume study medication with the 
first dose level reduction (3 tablets, 750 mg of study medication). 
• If toxicity recurs, hold study medication, and adjust or add medications to mitigate the 
toxicity. When resolved to ≤ Grade 1, resume study medication with the second dose 
level reduction (2 tablets, 500 mg of study medication). 
• If toxicity recurs despite aggressive medical management and 2 dose-level reductions, 
discontinue study medication. 
 
8.6.7 
Management of concomitant use with strong CYP3A4 inducers 
Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentine, phenobarbital) during ZYTIGA treatment. Although there are no 
clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers, 
because of the potential for an interaction, if a strong CYP3A4 inducer must be co- 
administered, increase the ZYTIGA dosing frequency to twice a day only during the co- 
administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). Reduce 
the dose back to the previous dose and frequency, if the concomitant strong CYP3A4 
inducer is discontinued. 
 
9. 
TREATMENT EVALUATION AND OUTCOMES 
All baseline evaluations will be performed within 30 days of the beginning of treatment except 
for laboratory tests and PSA which will be performed within 14 days of the beginning of 
treatment. For subsequent evaluations, the method of assessment and techniques will be the same 
as those used at baseline. 
Chest image and CT scan of abdomen and pelvis prior to, during and after study are to make sure 
patient does not have metastatic disease. The same method of assessment and the same technique 
will be used at baseline and for subsequent evaluations. 
By consensus, post-treatment PSA changes are not described as “responses.”52   Moreover, there 
are no clinically validated criteria for PSA “response” for subjects with non-castrate disease. As 
such, outcome reporting based on PSA percentage declines, or on the proportion of subjects 
showing normalization of an abnormal level does not apply to this subset of subjects. 
 
9.1 
Primary Endpoint 
The primary endpoint is progression-free survival (PFS) defined as an undetectable PSA (using a 
routine PSA assay) with non-castrate level of testosterone (>150 ng/dL) at 18 months from the 
time of treatment initiation. 
 
9.1.1 
Undetectable PSA 
An undetectable PSA is defined per the institution of participant registration. 
 
A confirmatory PSA must be drawn no less than 2 weeks following the first undetectable 
PSA. If that confirmatory PSA also exceeds the above parameter, then the subject is 
defined as a biochemical failure. 
 
If the confirmatory PSA fails to confirm a biochemical failure, then the subject will 
remain on study. 


45 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
9.1.2 
Soft tissue complete response 
In addition to an undetectable PSA, any pathological lymph nodes (whether target or 
non‐target) must have reduction in short axis to <10 mm (Complete Response per 
RECIST) in order to meet the criteria for PFS. 
 
Outcome in subjects who develop radiographically evident metastatic disease while on 
study will be considered treatment failures independent of their respective PSA values. 
 
9.2 
Secondary Endpoints 
9.2.1 
PSA response rate 
The percentage of patients with a non-castrate level of testosterone (>150 ng/dL) and an 
undetectable PSA at 8 months from PSA0 will be measured. 
 
9.2.2 
Testosterone and luteinizing hormone recovery rates 
Testosterone and LH recovery rates will be measured at 8 months from the start of 
randomization and at each month of the 10 month follow up period. 
 
9.2.3 
Quality of life 
Effects of each arm on quality of life, specifically: libido, potency, anxiety, depression, 
hot flashes, fatigue, joint swelling, muscle discomfort, diarrhea, and cough, and overall 
quality of life, will be assessed separately for each item as the change at 8 months from 
Day 1 Cycle 1, and as area under the curve (AUC) between Day 1 Cycle 1 and 8 months 
after Day 1 Cycle 1. 
 
9.2.4 
Safety profile 
Safety will be evaluated according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v4.0. Safety assessments will be based on medical review of 
adverse event reports and the results of vital sign measurements, physical examinations 
and clinical laboratory tests throughout the conduct of the study. The incidence of 
adverse events will be tabulated and reviewed for potential significance and clinical 
importance. The frequency and intensity of non-hematologic adverse events will be 
recorded until the subject has completed his participation in the study (See Section 11.5). 
 
9.3 
Tertiary Endpoint 
9.3.1 
Correlative tissue analysis 
Correlative tissue analysis with clinical outcomes while on study. 
 
10. 
DATA REPORTING AND REGULATORY REQUIREMENTS 
10.1 
Data Collection and Management 
Data collected during this study will be entered into a secure database. 
 
10.1.1 Electronic Case Report Forms (eCRFs) 
The participating sites will enter data remotely into electronic Case Report Forms 
(eCRFs) using the internet based MSK and PCCTC Caisis Electronic Data Capture 
(EDC) system. Completion Guidelines will be created by the PCCTC to provide 
instruction and guidance on how eCRFS should be completed. . Access and training for 
PCCTC Caisis EDC will be made available to participating sites upon local regulatory 
approval. The participating site PI is responsible for ensuring eCRFs are completed 
accurately and in a timely manner. 


46 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
10.1.2 
Source documents 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation will be made 
available to support the subject’s research record. Source documentation must include a 
minimum of two identifiers to allow for data verification. MSK will maintain the 
confidentiality of any subject-identifiable information it may encounter. 
 
10.1.3 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. The 
investigator will ensure that all regulatory documents and participating site IRB 
correspondences are maintained in an on site regulatory binder. After study closure, the 
participating sites must maintain all source documents, study related documents and 
eCRFs for 3 years. 
10.1.4 Source Documentation Submission for Registration at Participating Sites 
Participating sites should email any source documentation that corresponds to data 
entered at registration to PCCTC at PCCTC@mskcc.org within 24 hours (see Section 
4.1.2). 
10.1.5 Data Submission Timelines 
All baseline data should be transmitted to PCCTC within 24 hours of the visit. 
All study data should be transmitted to PCCTC within 14 days of visit except for SAE 
submission (see Section 8.3.1) as described in the Data Management Plan. 
10.1.6 Data Review and Queries 
PCCTC will review data and source documentation as it is submitted.  Data will be 
monitored and source data verified as necessary and discrepancies will be sent as queries 
to the participating sites. In addition, PCCTC will review data for logic, consistency, and 
obvious anomalies.  Queries will be sent by PCCTC to participating sites as needed. 
Participating sites should respond to data queries within 14 days of receipt. 
 
 
10.2 
Study Monitoring and Quality Assurance 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies 
set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data  
and Safety Monitoring of Clinical Trials” which can be found at:  
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research.  The MSKCC 
Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring%20P 
lans.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety, and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research quality assurance) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 


47 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
programs. There are several committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the MSKCC Research Council and Institutional Review Board. As a 
moderate risk trial, this study will be monitored by DSMC twice per year. 
Since therapeutic efficacy is a stated primary objective, all sites participant’s responses are 
subject to review by MSKCC’s Therapeutic Response Review Committee (TRRC).  Radiology 
and additional lab reports will need to be obtained from the participating sites for MSKCC TRRC 
review and confirmation of response assessment. These materials must be sent to MSKCC 
promptly upon request 
 
 
10.2.1 Data Auditing and Quality Assurance 
In addition to review by DSMC, PCCTC will conduct regularly scheduled remote 
monitoring every 6 weeks and audits as specified below.  Registration reports will be 
generated by the PCCTC to monitor subject accruals and the completeness of registration 
data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and the extent and accuracy of evaluations and follow-up 
will be monitored periodically throughout the study period, and potential problems will 
be brought to the attention of the Principal Investigator for discussion and action. 
Each site participating in the accrual of participants to this protocol will be audited at a 
minimum of 10% of all subjects, but at least 2 from each site will be 100% source data 
verified by the PCCTC.  Auditing will occur once shortly after initiation of subject 
recruitment at a site (once at least 2 subjects have been accrued and completed at least 1 
visit), annually during the study (or more frequently if indicated), and at the end or 
closeout of the trial, for protocol and regulatory compliance, data verification and source 
documentation. Audits may be accomplished in one of two ways: (1) sending source 
documents and research records for selected patients from participating sites to the 
PCCTC for audit, or (2) on-site auditing of selected patient records at participating sites. 
The audit will include a review of source documentation to evaluate compliance for: 
 
• 
Regulatory/IRB compliance (review of current protocol and amendments, Informed 
consent documents and procedures, annual continuing review reports, AEs/SAEs) 
• 
Protocol defined treatment compliance 
• 
Subject records 
1. Each subject is reviewed to determine that there is a signed and dated consent 
form 
2. Adherence to eligibility criteria 
3. Baseline, on study and follow-up protocol testing 
4. eCRF completion 
 
Audit findings will be reviewed by PI, Dr. Howard Scher, and disseminated to the Site 
PIs and staff. 
 
In addition, each participating site accruing participants to this protocol will be audited by 
MSK for protocol and regulatory compliance, data verification and source 
documentation. Audits of selected participant records may be conducted on-site or 
remotely. 


48 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
Audits will be conducted annually at minimum, and more often if significant and/or 
repeated findings are identified during monitoring visits. The number of participants 
audited will be determined by the outcome of monitoring visits and complexity of the 
protocol. 
 
Each audit will be summarized and a final report will be sent to the PI at the audited 
participating site within 30 days of the audit. The report will include a summary of 
findings, participant-specific case review, recommendations on any performance and/or 
shortcomings and request for corrective action, when necessary. When corrective action 
is required, the participating site must reply within 45 days of receipt of the audit report 
with their corrective action plan. 
 
 
11. 
STATISTICAL METHODS 
11.1 
General Considerations 
A randomized phase 2 screening design is used to compare the efficacy of abiraterone acetate and 
abiraterone acetate plus degarelix to degarelix alone for prostate cancer patients in the rising PSA 
clinical state. It is anticipated that the trial will remain open to accrual for 36 months with an 
additional 18 month follow-up after accrual closure.The primary endpoint for the study is 
achieving and maintaining a PSA level defined by the institution of participant registration for 
eighteen months from treatment initiation(PSA0). A patient that achieves and maintains a PSA0 
will be denoted as a success in this design. Patients that are not followed through the 18 month 
follow-up mark will be counted as failures. 
 
Unless otherwise specified, all continuous endpoints will be summarized using descriptive 
statistics, which will include the number of subjects, mean, standard deviation, median, 
minimum, and maximum. All categorical endpoints will be summarized using frequencies and 
percentages. The baseline measurement will be the last value on or before the date of first study 
treatment. 
 
11.2 
Sample Size Determination 
One hundred and twenty patients will be randomized to the three treatment groups. Each 
abiraterone acetate group will be compared to the degarelix alone group. With 40 patients per 
group, it is assumed that the probability of a success in the degarelix alone group is ≤ 0.25 and the 
probability of a success is at least 0.20 greater than degarelix alone in the abiraterone-based 
groups. Under these projections, there is greater than an 80% chance of finding for either 
abiraterone-based treatment relative to degarelix alone using Fisher’s exact test with a one-sided 
0.20 significance level. The type 1 and type 2 errors are applied separately to each abiraterone 
acetate group comparison. 
 
The choice of a 0.20 significance level is intended to reduce the sample size required for this 
comparative study. A significant outcome does not imply definitive evidence of superiority for 
either abiraterone-based treatment relative to degarelix alone due to this high type 1 error, but 
instead provides sufficient evidence that testing of abiraterone acetate should proceed. 
 
11.3 
Analysis Population 
The analysis population will include all subjects who receive at least 1 dose of study drug. 


49 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
11.4 
Demographics and Baseline Characteristics 
Demographic variables will include age, race, ethnicity, height, and weight. Baseline disease 
characteristics will include time from diagnosis, time from radical prostatectomy to PSA 
progression and time from radical prostatectomy to initiation of study drug. 
 
11.5 
Safety Analysis 
11.5.1 Adverse events 
Safety analysis will be summarized using the Safety Population defined as any patient 
receiving any part of study treatment. 
 
Extent of exposure to study treatment will be summarized and details will be provided. 
Treatment emergent adverse events (AEs) are those events that occur or worsen on or 
after first dose of study drug up through 30 days post last dose. Adverse events will be 
coded using the MedDRA coding system and all AEs will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
v4.0. 
 
11.5.2 Clinical laboratory tests 
All Grade 3 and 4 abnormal laboratory test results will be reported according to the NCI- 
CTCAE Version 4.0 criteria. 
 
12. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS 
12.1 
Roles and Responsibilities 
12.1.1 Lead Site/Sponsor Principal Investigator 
The Sponsor Principal Investigator at the lead site is responsible for performing the 
following tasks: 
• 
Responsibility for the overall conduct of the study at all participating sites and 
for monitoring the progress of the study 
• 
Reviewing Adverse Events (AEs) and Serious Adverse Events (SAEs) 
• 
Reviewing data from all participating sites 
 
12.1.2 PCCTC 
The PCCTC is responsible for performing the following tasks: 
• 
Ensuring that IRB approval has been obtained at each participating site prior to 
the first patient registration at that site, and maintaining copies of IRB approvals 
and required regulatory documents from each site. 
• 
Managing subject registration 
• 
Developing and maintaining Clinical Data Management documents and 
procedures 
• 
CRF development, setup of study database, and subsequent design changes 
• 
Participating in review of content of the CRF against the protocol requirements 
• 
EDC system administration (user/site accounts setup, maintenance and 
revocation) 
• 
Data review, cleaning, query management and resolution 
• 
Establishing procedures for documentation, reporting and submitting of AE’s 
and SAEs to the PCCTC. 
• 
Reviewing AEs and SAEs 
• 
Submitting AEs and SAEs to Janssen 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
50 of 69 
12-187 A(15) Protocol.DOCX 
 
 
• 
• 
Training participating sites on EDC 
• 
Collecting and compiling data from each participating site 
• 
Data reviewing from all participating sites 
• 
Facilitating audits by securing selected source documents and research records 
from participating sites for audit, or by auditing at participating sites. 
• 
Overseeing the management of study drug at pariticipating sites 
 
12.1.3 Participating Sites 
Participating sites are responsible for performing the following tasks: 
• 
Following the protocol as written, the guidelines of Good Clinical Practice (GCP), 
and applicable Standard Operating Procedures (SOPs). Registering all patients 
with the PCCTC by submitting the eligibility checklist, supporting source 
documentation, and signed informed consent promptly. 
• 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the 
protocol 
• 
Maintaining regulatory binders on site and providing copies of all required 
documents to the PCCTC 
• 
Collecting and submitting data according to the schedule specified by the 
protocol 
• 
Responding to queries in a timely manner 
 
12.2 
Ethical Considerations 
This study will be conducted in compliance with the protocol, GCP guidelines established by the 
International Conference on Harmonisation, and the ethical standards set forth in the Declaration 
of Helsinki 2004 (available at: www.laakariliitto.fi/e/ethics/helsinki.html). 
 
12.3 
Regulatory Documentation 
Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the MSK 
Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol document and each 
participating site will utilize that document. 
 
The following documents must be provided to PCCTC before the participating site can be initiated and 
begin enrolling participants: 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 
• 
Participating Site IRB approved informed consent form and HIPAA authorization 
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 
• 
Curriculum vitae and medical licenses for each investigator and consenting professional 
• 
Documentation of Human Subject Research Certification training for investigators and key 
staff members at the participating site 
• 
Documentation of Good Clinical Practice (GCP) training for the PI and co-PI at the 
participating site 
• 
Participating site laboratory certifications and normals 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
51 of 69 
12-187 A(15) Protocol.DOCX 
 
 
Upon receipt of the required documents, PCCTC will submit a participating site activation 
request to MSKCC. Once approved, MSKCC will formally contact PCCTC and grant the site 
permission to proceed with enrollment. 
 
12.4 
Protocol Amendments 
Each change to the protocol document must be organized and documented by the PCCTC, 
reviewed and approved by Janssen Scientific Affairs, LLC, and approved by the MSKCC 
IRB/PB. Protocol amendments that affect MSK only (e.g. change in MSK Co-Investigator, MSK 
translation, etc.) do not require IRB review at the participating sites. All other protocol 
amendments will be immediately distributed to each participating site upon receipt of MSK 
IRB/PB approval. 
Each participating sites must obtain approval for all amendments from their IRB within 90 
calendar days of MSK IRB/PB approval. If the amendment is the result of a safety issue or makes 
eligibility criteria more restrictive, participating sites will not be permitted to continue enrolling 
new participants until site IRB approval of the revised protocol document granted and submitted 
to the PCCTC, who will in turn submit the approval documenaton to MSKCC. 
 
The following documents must be provided to PCCTC for each amendment within the stated timelines: 
• 
Participating Site IRB approval 
• 
Participating Site IRB approved informed consent form and HIPAA authorization 
 
PCCTC is responsible for submitting all participating site local IRB approvals and/or 
acknowledgments to MSK upon receipt 
12.5 
Additional IRB Correspondences 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to PCCTC within 7 days of 
expiration. Failure to submit the re-approval in the stated timeline will result in suspension of new 
participant enrollment. PCCTC is responsible for submitting all participating site local IRB 
approvals and/or acknowledgments to MSK upon receipt. 
 
Deviations 
A protocol deviation on this study is defined as any incident involving non-adherence to an IRB 
approved protocol. Deviations typically do not have a significant effect on the rights, safety, or 
welfare of research participants or on the integrity of the resultant data. Deviations that represent 
unanticipated problems involving risks to participants or others, or serious adverse events should 
be reported according to sections 8.5.1 and 8.5.4. 
 
Deviations that do not adversely affect the rights and/or welfare of the participant or the scientific 
validity of the study and are related to protocol scheduling changes outside of the allowed  
window due to a holiday (e.g., New Year’s, Thanksgiving, etc.) and/or inclement weather or other 
natural event do not require reporting to the PCCTC. However, they must be clearly documented 
in the patient’s medical record. 
 
Prospective Deviations 
 
Deviations to the research protocol that involve patient eligibility, an informed consent procedure 
change, and/or treatment/pharmacy alterations that are not allowed by the protocol require 
prospective approval from the MSK IRB/PB prior to the change being carried out. Participating 
sites should contact PCCTC who will in turn seek approval from the MSK IRB/PB. 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
52 of 69 
12-187 A(15) Protocol.DOCX 
 
 
Retrospective Deviations 
 
Deviations that include a change or departure from the research protocol without prior approval 
from the MSK IRB/PB are considered retrospective deviations. Retrospective deviations should 
be reported to PCCTC as soon as possible, who will in turn report the deviation to the MSK 
IRB/PB as per MSK guidelines. 
 
Participating Site IRB Reporting 
 
Participating sites should report all deviations to their institution’s IRB per local guidelines. 
Approvals/acknowledgments from the participating site IRB for protocol deviations should be 
submitted to PCCTC who will in turn submit to MSK IRB/PB upon receipt. 
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according to local 
guidelines, and submit copies of that correspondence to PCCTC. PCCTC is responsible for submitting 
all participating site local IRB correspondences to MSK upon receipt. 
 
12.6 
Written Informed Consent 
Patients will be required to sign and date (in triplicate) a statement of informed consent that meets 
the requirements of the Code of Federal Regulations (Federal Register Vol. 46, No. 17, January 
27, 1981, part 50) and the IRB. The medical record will include a statement that written informed 
consent was obtained (and document the date that it was obtained) before the patient is enrolled in 
the study. The original signed document will become part of the patient’s medical record, a copy 
will be forwarded to the lead site pursuant to registration and to the PCCTC, and a copy will be 
sent home with each patient. Details regarding Informed Consent can be found in Section 6.1. 
Informed Consent Procedures for Participating Sites 
 
The investigators listed on the Consenting Professionals Lists at each participating site may 
obtain informed consent and care for the participants according to Good Clinical Practice and 
protocol guidelines 
 
12.7 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. After this discussion, they will be asked to 
sign a research authorization/HIPAA form. The original signed documents will become part of 
the patient’s medical records, and each patient will receive a copy of the signed documents. The 
use and disclosure of protected health information will be limited to the individuals described in 
the research authorization form. The research authorization form must be completed by the 
principal investigator and approved by the IRB. 
 
12.8 
Terminating or Modifying the Study 
Adverse event and laboratory data from this trial will be assessed by the lead site on an ongoing 
basis. SAEs will be reviewed as they are reported to the lead site/sponsor and PCCTC and the 
principal investigator will make an assessment regarding the safety of continuing or modifying 
the study. This assessment will be shared with the investigators either in writing or as part of a 
teleconference. Should the assessment of either the lead site or the principal investigator be that 
the study should be terminated, the study will be closed to further accrual. Patients who are 
receiving an investigational agent will be assessed individually by the investigator to see if it is in 
the patients’ best interest to continue, which might be the case for a patient that is responding to 
the intervention. Follow-up safety assessments will be performed for all patients who are 
terminated from the study prematurely. 


53 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
12.9 
Noncompliance 
If a participating site is noncompliant with the protocol document, accrual privileges may be suspended 
and/or contract payments may be withheld, until the outstanding issues have been resolved. 
 
 
13. 
REFERENCES 
1. 
Holzbeierlein J, Lal P, LaTulippe E, et al: Gene expression analysis of human prostate 
carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy 
resistance. Am J Pathol 164:217-27, 2004 
2. 
McLeod D, Zinner N, Tomera K, et al: A phase 3, multicenter, open-label, randomized 
study of abarelix versus leuprolide acetate in men with prostate cancer. Urology 58:756-61, 2001 
3. 
Tomera K, Gleason D, Gittelman M, et al: The gonadotropin-releasing hormone 
antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: 
initial results of endocrinological and biochemical efficacies in patients with prostate cancer. J Urol 
165:1585-9, 2001 
4. 
Trachtenberg J, Gittleman M, Steidle C, et al: A phase 3, multicenter, open label, 
randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J 
Urol 167:1670-4, 2002 
5. 
Kim D, Gregory CW, French FS, et al: Androgen receptor expression and cellular 
proliferation during transition from androgen-dependent to recurrent growth after castration in the 
CWR22 prostate cancer xenograft. Am J Pathol 160:219-26, 2002 
6. 
Stephenson AJ, Kattan MW, Eastham JA, et al: Prostate cancer-specific mortality after 
radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol 27:4300-5, 
2009 
7. 
D'Amico AV, Moul J, Carroll PR, et al: Cancer-specific mortality after surgery or 
radiation for patients with clinically localized prostate cancer managed during the prostate-specific 
antigen era. J Clin Oncol 21:2163-72, 2003 
8. 
Crook J, Ludgate C, Malone S, et al: Final report of multicenter Canadian Phase III 
randomized trial of 3 versus 8 months of neoadjuvant androgen deprivation therapy before conventional- 
dose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 73:327-33, 2009 
9. 
Freedland SJ, Moul JW: Prostate specific antigen recurrence after definitive therapy. J 
Urol 177:1985-91, 2007 
10. 
Yossepowitch O, Bianco FJ, Jr., Eggener SE, et al: The natural history of noncastrate 
metastatic prostate cancer after radical prostatectomy. Eur Urol 51:940-7; discussion 947-8, 2007 
11. 
Antonarakis ES, Feng Z, Trock BJ, et al: The natural history of metastatic progression in 
men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up. BJU Int, 
2011 
12. 
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant 
chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-72, 2005 
13. 
Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast 
cancer. N Engl J Med 352:2302-13, 2005 
14. 
Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as 
adjuvant treatment for colon cancer. N Engl J Med 350:2343-51, 2004 
15. 
Dematteo RP, Ballman KV, Antonescu CR, et al: Adjuvant imatinib mesylate after 
resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo- 
controlled trial. Lancet 373:1097-104, 2009 
16. 
Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in 
resected non-small-cell lung cancer. N Engl J Med 352:2589-97, 2005 


54 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
17. 
Sasagawa I, Kubota Y, Nakada T, et al: Influence of luteinizing hormone-releasing 
hormone analogues on serum levels of prostatic acid phosphatase and prostatic specific antigen in patients 
with metastatic carcinoma of the prostate. Int Urol Nephrol 30:745-53, 1998 
18. 
Klotz L, Boccon-Gibod L, Shore ND, et al: The efficacy and safety of degarelix: a 12- 
month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate 
cancer. BJU Int 102:1531-8, 2008 
19. 
Scher HI, Heller G: Clinical states in prostate cancer: toward a dynamic model of disease 
progression. Urology 55:323-7, 2000 
20. 
Armstrong AJ, Garrett-Mayer E, de Wit R, et al: Prediction of survival following first- 
line chemotherapy in men with castration-resistant metastatic prostate cancer. Clin Cancer Res 16:203-11, 
2010 
21. 
Halabi S, Small EJ, Kantoff PW, et al: Prognostic model for predicting survival in men 
with hormone-refractory metastatic prostate cancer. J Clin Oncol 21:1232-7, 2003 
22. 
Smaletz O, Scher HI, Small EJ, et al: Nomogram for overall survival of patients with 
progressive metastatic prostate cancer after castration. J Clin Oncol 20:3972-82, 2002 
23. 
Shulman MJ, Benaim EA: Prognostic model of event-free survival for patients with 
androgen-independent prostate carcinoma. Cancer 103:2280-6, 2005 
24. 
Eastham JA, Scardino PT, Kattan MW: Predicting an optimal outcome after radical 
prostatectomy: the trifecta nomogram. J Urol 179:2207-10; discussion 2210-1, 2008 
25. 
Slovin SF, Wilton AS, Heller G, et al: Time to detectable metastatic disease in patients 
with rising prostate-specific antigen values following surgery or radiation therapy. Clin Cancer Res 
11:8669-73, 2005 
26. 
Freedland SJ, Humphreys EB, Mangold LA, et al: Death in patients with recurrent 
prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their 
associated contributions to all-cause mortality. J Clin Oncol 25:1765-71, 2007 
27. 
D'Amico AV, Moul JW, Carroll PR, et al: Surrogate end point for prostate cancer- 
specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst 95:1376-83, 2003 
28. 
Ryan CJ, Smith A, Lal P, et al: Persistent prostate-specific antigen expression after 
neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression. 
Urology 68:834-9, 2006 
29. 
Titus MA, Schell MJ, Lih FB, et al: Testosterone and dihydrotestosterone tissue levels in 
recurrent prostate cancer. Clin Cancer Res 11:4653-7, 2005 
30. 
Geller J, Albert J, Nachtsheim D, et al: Steroid levels in cancer of the prostate--markers 
of tumor differentiation and adequacy of anti-androgen therapy. Prog Clin Biol Res 33:103-11, 1979 
31. 
Suzuki K, Nishiyama T, Hara N, et al: Importance of the intracrine metabolism of adrenal 
androgens in androgen-dependent prostate cancer. Prostate Cancer Prostatic Dis 10:301-6, 2007 
32. 
Nelson PS, Han D, Rochon Y, et al: Comprehensive analyses of prostate gene expression: 
convergence of expressed sequence tag databases, transcript profiling and proteomics. Electrophoresis 
21:1823-31, 2000 
33. 
Montgomery RB, Mostaghel EA, Vessella R, et al: Maintenance of intratumoral 
androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 
68:4447-54, 2008 
34. 
Stanbrough M, Bubley GJ, Ross K, et al: Increased expression of genes converting 
adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 66:2815-25, 2006 
35. 
Mostaghel EA, Page ST, Lin DW, et al: Intraprostatic androgens and androgen-regulated 
gene expression persist after testosterone suppression: therapeutic implications for castration-resistant 
prostate cancer. Cancer Res 67:5033-41, 2007 
36. 
U.S. Food and Drug Administration Center for Drug Evaluation and Research: Viadur 
(Leuprolide Acetate Implant) Drug Approval Package, Application No.:  21-088,  
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/02-1088_Vidaur.cfm, March 3, 2000 


55 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
37. 
Eligard (Leuprolide Acetate) Injectable Suspension Drug Approval Package, 
Application No.:  21-343, http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-343_Eligard.cfm, 
U.S. Food and Drug Administration Center for Drug Evaluation and Research, January 23, 2002 
38. 
Degarelix Injection Drug Approval Package, Application No.:  022201,  
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022201s000_TOC.cfm, U.S. Food and Drug 
Administration Center for Drug Evaluation and Research, December 24, 2008 
39. 
Klotz LH, O'Callaghan CJ, Ding K, et al: A phase III randomized trial comparing 
intermittent versus continuous androgen suppression for patients with PSA progression after radical 
therapy: NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013 J Clin 
Oncol 29:abstr 3, 2011 
40. 
Hussain M, Goldman B, Tangen C, et al: Prostate-specific antigen progression predicts 
overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group Trials 
9346 (Intergroup Study 0162) and 9916. J Clin Oncol 27:2450-6, 2009 
41. 
Bruchovsky N, Klotz L, Crook J, et al: Locally advanced prostate cancer--biochemical 
results from a prospective phase II study of intermittent androgen suppression for men with evidence of 
prostate-specific antigen recurrence after radiotherapy. Cancer 109:858-67, 2007 
42. 
Attard G, Reid AH, Yap TA, et al: Phase I clinical trial of a selective inhibitor of CYP17, 
abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. 
J Clin Oncol 26:4563-71, 2008 
43. 
Attard G, Reid AH, A'Hern R, et al: Selective inhibition of CYP17 with abiraterone 
acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 27:3742-8, 
2009 
44. 
Reid AH, Attard G, Danila DC, et al: Significant and sustained antitumor activity in post- 
docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 
28:1489-95, 2010 
45. 
de Bono JS, Logothetis CJ, Molina A, et al: Abiraterone and increased survival in 
metastatic prostate cancer. N Engl J Med 364:1995-2005, 2011 
46. 
O'Donnell A, Judson I, Dowsett M, et al: Hormonal impact of the 17alpha- 
hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J 
Cancer 90:2317-25, 2004 
47. 
Mohler JL, Gregory CW, Ford OH, 3rd, et al: The androgen axis in recurrent prostate 
cancer. Clin Cancer Res 10:440-8, 2004 
48. 
Stigliano A, Gandini O, Cerquetti L, et al: Increased metastatic lymph node 64 and 
CYP17 expression are associated with high stage prostate cancer. J Endocrinol 194:55-61, 2007 
49. 
Lange PH, Ercole CJ, Lightner DJ, et al: The value of serum prostate specific antigen 
determinations before and after radical prostatectomy. J Urol 141:873-9, 1989 
50. 
Zincke H, Oesterling JE, Blute ML, et al: Long-term (15 years) results after radical 
prostatectomy for clinically localized (stage T2c or lower) prostate cancer. J Urol 152:1850-7, 1994 
51. 
Sloan JA, Loprinzi CL, Kuross SA, et al: Randomized comparison of four tools 
measuring overall quality of life in patients with advanced cancer. J Clin Oncol 16:3662-73, 1998 
52. 
Scher HI, Eisenberger M, D'Amico AV, et al: Eligibility and outcomes reporting 
guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: recommendations 
from the Prostate-Specific Antigen Working Group. J Clin Oncol 22:537-56, 2004 
53. 
Ryan CJ, Smith, MR, de Bono, et al: Abiraterone in metastatic prostate cancer without 
previous chemotherapy. N Engl J Med 368: 138-48, 2013 


56 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
APPENDIX A: ECOG PERFORMANCE STATUS SCALE 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
% 
Description 
0 
Normal activity. Fully active, able to 
continue all predisease performance without 
restriction. 
100 
Normal, no complaints, no evidence of 
disease 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity but ambulatory 
and able to carry out work of a light or 
sedentary nature (eg, light housework,  
office work). 
80 
Normal activity with effort, some signs or 
symptoms of disease 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
2 
In bed < 50% of the time. Ambulatory and 
capable of all self-care but unable to carry 
out any work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance but is able to 
care for most needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time. Capable of only 
limited self-care, confined to bed or chair 
> 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization indicated. 
Death not imminent. 
4 
100% bedridden. Completely disabled, 
cannot carry on any self-care, totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 


57 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
APPENDIX B: PRO SURVEY 
 


58 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
 


59 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
60 of 69 
12-187 A(15) Protocol.DOCX 
 
 
 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
61 of 69 
12-187 A(15) Protocol.DOCX 
 
 
APPENDIX C: JANSSEN SERIOUS ADVERSE EVENT REPORT FORM (FOR 
PCCTC) 
 


62 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 


63 of 69 
12-187 A(15) Protocol.DOCX 
 
 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 


64 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 


65 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
 
 
APPENDIX D: PCCTC SAE REPORT FORM FOR ALL SITES 
 
Please see the PCCTC Serious Adverse Event Report Form 


66 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
APPENDIX E: GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
 
ACTH 
adrenocorticotropic hormone 
ADR 
adverse drug reaction 
ADT 
androgen-deprivation therapy 
AE 
adverse event 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AR 
androgen receptor 
ASAEL 
Agent Specific Adverse Event List 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C02 
carbon dioxide 
CAEPR 
Comprehensive Adverse Event and Potential Risks 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
Cl 
chloride 
CLIA 
Clinical Laboratory Improvement Amendments 
Cr 
creatinine 
Cmax 
maximum plasma concentration 
CRDB 
Clinical Research Database 
CRF 
case report form 
CRPC 
castration resistant prostate cancer 
CT 
computerized tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome p-450 
dL 
deciliter 
DHEA 
dehydroepiandrosterone 
DHEA-S 
dehydroepiandrosterone sulfate 
DHT 
dihydrotestosterone 
DLT 
dose-limiting toxicity 
DSM 
data and safety monitoring 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EKG 
electrocardiogram 
EORTC 
European Organisation for Research and Treatment of Cancer 
FDA 
Food and Drug Administration 
FDG-PET 
2-[18F]fluoro-2-deoxyglucose positron emitting tomography 
FDHT 
18-fluoro-dehydrotestosterone 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 


67 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
GnRH 
gonadotropin-releasing hormone 
Hct 
hematocrit 
Hgb 
hemoglobin 
HEENT 
head, eyes, ears, nose and throat examination 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
K+ 
potassium 
KLK1 
kallikrein 1 


68 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LH 
luteinizing hormone 
LVEF 
left ventricular ejection fraction 
mCRP 
C 
metastatic castration-resistant prostate cancer 
MRI 
magnetic resonance imaging 
MSKC 
C 
Memorial Sloan-Kettering Cancer Center 
MTD 
maximum tolerated dose 
MUGA 
multi gated acquisition scan 
N 
number of subjects or observations 
Na 
sodium 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NYHA 
New York Heart Association 
NSAID 
nonsteroidal anti-inflammatory drug 
PCCT 
C 
Prostate Cancer Clinical Trials Consortium 
PCWG 
Prostate Cancer Working Group 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
principal investigator 
PK 
pharmacokinetics 
PO 
per os (by mouth) 
PQC 
product quality complaint 
PR 
partial response 
PSA 
prostate-specific antigen 
PSA- 
DT 
prostate-specific antigen doubling time 
PSMA 
prostate specific membrane antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QOL 
quality of life 
RBC 
red blood cell 
RECIS 
T 
Response Evaluation Criteria in Solid Tumors 
RP 
radical prostatectomy 
RPC 
Research Program Coordinator 
RSA 
Research Study Assistant 
SAE 
serious adverse event 
SC 
subcutaneous 
SUV 
standardized uptake value 


69 of 69 
12-187 A(15) Protocol.DOCX 
Memorial Sloan Kettering Cancer Center 
IRB Protocol #: 12-187 A(15) 
Approved: 30-JAN-2017 
 
 
 
T 
testosterone 
TB 
pulmonary tuberculosis 
TDP 
time to disease progression 
TGP 
prostate-specific transglutaminase 
TMPR 
SS2 
transmembrane protease, serine 2 
ULN 
upper limit of normal 
WBC 
white blood cell