Open Label Pharmacodynamic Study of Abiraterone Acetate in the Treatment of Metastatic, Castration Resistant Prostate Cancer
Phase: PHASE2
Conditions: Hormone-Resistant Prostate Cancer, Metastatic Prostate Carcinoma, Recurrent Prostate Carcinoma, Stage IV Prostate Adenocarcinoma
Sponsor: University of Washington

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 1 of 69 
 
Clinical Study Protocol 
Study Title: 
OPEN LABEL PHARMACODYNAMIC STUDY OF  ABIRATERONE 
ACETATE IN THE TREATMENT OF METASTATIC, CASTRATION 
RESISTANT PROSTATE CANCER 
Study Number: 
0801 
Cancer Consortium # 7639  
Study Phase: 
2 
Product Name: 
Abiraterone acetate 
IND Number: 
Exempt 
Indication: 
Treatment of metastatic, castration resistant prostate cancer  
Protocol version 
Current Version Date:  09/10/2015 
v. 6.0 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 2 of 69 
 
SYNOPSIS 
Study 
Title: 
Open label pharmacodynamic study of abiraterone acetate in the treatment of metastatic, castration 
resistant prostate cancer.  
Study:  Investigator-initiated, Phase II 
Funding support and abiraterone acetate provided by Janssen Services 
Primary Objective: 
To determine the magnitude of tissue testosterone suppression by abiraterone acetate in metastatic 
CRPC (resistant to LHRH agonist or orchiectomy ± antiandrogen) after one month of treatment to 
establish tissue based mechanism of action. 
Exploratory Objectives: 
 To determine the ability of abiraterone acetate to suppress tumor testosterone after 12 weeks 
of treatment. 
 To determine tissue testosterone from metastasis at time of radiographic progression during 
abiraterone acetate treatment.  
 To determine response to dose escalation of abiraterone acetate at clinical progression   
 To determine potential mechanisms of resistance to abiraterone acetate by analyzing 
pharmacokinetics at clinical progression, tissue androgen levels at baseline and at radiographic 
progression, evaluating wild type and splice variant AR levels at baseline and at time of 
progression and cDNA microarray at progression 
 To determine if microRNA acquired from peripheral blood reflect molecular changes in tumor 
metastases and are a potential biomarker for mechanisms of sensitivity and resistance. 
 To evaluate pharmacokinetics of dose escalated abiraterone at 1000 mg twice daily 
 
Study Population: 
Men with metastatic, castration resistant prostate cancer amenable to biopsy 
 Investigational Product, Dose and Mode of Administration: 
Abiraterone acetate, 1000 mg/dose (4 x 250-mg tablets) given orally, at least 2 hours before a 
meal and 1 hour after a meal, initially given once a day, then twice a day at dose escalation. 
 Abiraterone acetate will be administered with prednisone 5 mg given orally twice daily 
Duration of Treatment: 
All patients will undergo pretreatment metastasis biopsy. All patients will receive Lupron or 
orchiectomy combined with abiraterone acetate and prednisone until radiologic or clinical progression 
as defined by Prostate Cancer Working Group 2 criteria.  Patients will be sequentially enrolled in 
three cohorts, to undergo repeat biopsy at 4 weeks (cohort 1), 12 weeks (cohort 2) or at progression 
(cohort 3).  Dose escalation after initial radiographic progression for all patients is allowed until there 
is evidence of additional radiographic or clinical progression. 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 3 of 69 
 
Endpoints 
Primary Endpoint:  
 Tissue testosterone 
Exploratory endpoints 
 Tissue and serum DHT, androstenedione, DHEA,  
 PSA kinetics  and radiologic changes by RECIST 1.1  
 Androgen receptor – wild type and splice variant levels 
 cDNA microarray analysis, RT-PCR 
 MicroRNA 
 Pharmacokinetics of abiraterone 
 
Statistical Methods for sample size calculation 
The primary endpoint is evaluation of the suppression of tissue testosterone from baseline (the last 
value on or before the date of first study treatment) to the 4-week time point. Sample size calculations 
for this endpoint are based on xenograft studies of abiraterone acetate. Planned analysis of primary 
and exploratory endpoints involves numerical and graphical summaries and standard statistical 
hypothesis tests and linear-model-based inference. 
Basal tissue testosterone and testosterone after abiraterone acetate treatment at response were derived 
from xenograft studies of abiraterone acetate effect in castrate male mice. Baseline tissue testosterone 
in untreated CRPC xenografts was 0.687 ± 0.364 (mean ± SD) pg/mg, approximating that seen in 
human CRPC metastases. Nadir tissue testosterone after 7–21 days was 0.027 ± 0.009 pg/mg, 
approximating 4-week levels. Using the SD of testosterone derived from untreated observations 
(0.364 pg/mg), 6 patients provide 94% power to detect the anticipated 0.660 pg/mg difference in 
tissue testosterone relative to baseline based on a 2-sided paired t-test with alpha 5%.  Ten patients per 
cohort will be included to account for potentially unproductive biopsies. 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 4 of 69 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................7 
1 
INTRODUCTION ...........................................................................................................10 
1.1 
Advanced Prostate Cancer and Efficacy of Standard Androgen Deprivation .......10 
1.2 
Abiraterone acetate (JNJ212082) ...........................................................................11 
1.2.1 
Dosing Rationale ........................................................................................14 
1.2.2 
Concurrent Prednisone .............................................................................14 
1.3 
Rationale for Study Design ....................................................................................15 
2 
STUDY OBJECTIVES ....................................................................................................16 
2.1 
Primary Objective ..................................................................................................16 
2.2 
Exploratory Objectives ..........................................................................................16 
3 
INVESTIGATIONAL PLAN ..........................................................................................16 
3.1 
Overall Study Design and Plan ..............................................................................16 
3.1.1 
Primary Endpoint ......................................................................................17 
3.1.2 
Exploratory Endpoints ..............................................................................17 
4 
STUDY POPULATION SELECTION ...........................................................................18 
4.1 
Study Population ....................................................................................................18 
4.2 
Inclusion Criteria ...................................................................................................18 
4.3 
Exclusion Criteria ..................................................................................................20 
5 
STUDY TREATMENT(S) ..............................................................................................20 
5.1 
Description of Treatment(s) ...................................................................................20 
5.1.1 
Abiraterone acetate ....................................................................................20 
5.1.2 
Prednisone ..................................................................................................21 
5.2 
Treatments Administered .......................................................................................21 
5.2.1 
Abiraterone acetate ....................................................................................21 
5.2.2 
Prednisone ..................................................................................................21 
5.3 
Concomitant Therapy.............................................................................................22 
5.4 
Restrictions ............................................................................................................22 
5.5 
Potential for Drug-Drug Interactions .....................................................................22 
5.6 
Treatment Compliance ...........................................................................................23 
5.7 
Packaging and Labeling .........................................................................................23 
5.8 
Storage ...................................................................................................................23 
5.8.1 
Pharmacy Storage Requirements .............................................................24 
5.8.2 
Storage Requirements For The Patient ...................................................24 
5.9 
Handling abiraterone acetate tablets ......................................................................24 
5.10 
Investigational Product Retention and Accountability at Study Site .....................24 
6 
STUDY PROCEDURES .................................................................................................25 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 5 of 69 
 
6.1 
Informed Consent...................................................................................................25 
6.2 
Medical History .....................................................................................................25 
6.3 
Physical Examination.............................................................................................25 
6.4 
Clinical Laboratory Tests .......................................................................................25 
6.4.1 
Laboratory Parameters .............................................................................26 
6.4.2 
Sample Collection, Storage, and Shipping ...............................................26 
6.5 
Efficacy Assessments.............................................................................................27 
6.5.1 
The Primary Endpoint Measure...............................................................27 
6.5.2 
Exploratory Endpoint Measures ..............................................................28 
6.6 
Safety Assessments ................................................................................................28 
6.7 
Safety Data Collection, Recording and Reporting .................................................29 
6.7.1 
Definition of Adverse Event (AE) .............................................................29 
6.7.2 
Definition of a Serious Adverse Event .....................................................30 
6.7.3 
Suspected Unexpected Serious Adverse Events (SUSARS) ...................31 
6.7.4 
Reporting Procedures for Adverse Events ..............................................31 
6.7.5 
Management of Study Drug-Related Events ...........................................35 
6.8 
DOSAGE FORMS AND Criteria for Discontinuation of Study ...........................38 
6.9 
Withdrawal from Study..........................................................................................38 
7 
STUDY ACTIVITIES .....................................................................................................38 
7.1 
Study Visit Overview .............................................................................................38 
7.2 
Pre-Treatment Biopsy ............................................................................................40 
7.3 
Treatment Period ....................................................................................................40 
7.3.1 
Visit 1 (Study Day 1) ..................................................................................40 
7.3.2 
Subsequent visits ........................................................................................40 
7.3.3 
Pharmacokinetics .......................................................................................41 
7.3.4 
Dose escalation ...........................................................................................42 
8 
PLANNED STATISTICAL METHODS ........................................................................43 
8.1 
General Considerations ..........................................................................................43 
8.2 
Determination of Sample Size ...............................................................................43 
8.3 
Analysis Populations ..............................................................................................43 
8.4 
Demographics and Baseline Characteristics ..........................................................44 
8.5 
Safety Evaluations .................................................................................................44 
9 
REFERENCE LIST .........................................................................................................45 
10 APPENDICES .................................................................................................................48 
APPENDIX 1 - SCHEDULE OF EVENTS ............................................................................48 
APPENDIX 2 - TISSUE ACQUISITION SOP .......................................................................50 
APPENDIX 3 - TREATMENT SCHEMATIC .......................................................................51 
APPENDIX 4 - ADVERSE EVENTS .....................................................................................52 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 6 of 69 
 
APPENDIX 5 – PROGRESSION AND RESPONSE CRITERIA .........................................60 
APPENDIX 6 - METHOD FOR PHARMACOKINETIC SAMPLE COLLECTION AND HANDLING
..........................................................................................................................................65 
APPENDIX 7 – SUMMARY OF CHANGES ........................................................................68 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 7 of 69 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACTH 
Adrenocorticotropic hormone 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
AR 
Androgen receptor 
AST 
Aspartate aminotransferase (SGOT) 
BUN 
Blood urea nitrogen 
C 
Celsius 
CBC 
Complete blood count 
CrCl 
Creatinine clearance 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRPC 
Castration resistant prostate cancer 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
Dehydroepiandrosterone 
ECG 
Electrocardiogram 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
HEENT 
Head, Eyes, Ears, Nose, Throat 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
IND 
Investigational New Drug  
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LDH 
Lactic dehydrogenase 
LHRH 
Luteinizing hormone releasing hormone 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 8 of 69 
 
LN 
Lymph Node 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
OS 
Overall survival 
PFS 
Progression Free Survival 
PR 
Partial Response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PSA 
Prostate Specific Antigen 
SAE 
Serious adverse event 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SUSAR 
Suspected unexpected serious adverse reaction 
ULN 
Upper limit of normal 
WBC 
White blood cell (count) 
 
 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 9 of 69 
 
Study  
Chairs: 
Principal investigators; 
Bruce Montgomery, MD (Sponsor-investigator) 
Elahe Mostaghel, MD, PhD 
Co-investigators. 
Celestia Higano, M.D. 
Peter Nelson, M.D. 
 
Evan Yu, M.D. 
Heather Cheng, M.D,, PhD 
Michael Schweizer, M.D. 
James Dreschler, ARNP 
Tanisha Mojica ARNP 
Susan Treharne, ARNP 
 
Study Coordinator: 
Jessica Maes , CCRC 
Hiep Nguygen, CCRC 
 
Statistics 
Roman Gulati, PhD 
 
Study sites 
Seattle Cancer Care Alliance 
Prostate Oncology Center 
1959 NE Pacific St.  
Seattle, WA 98195 
206-598-6088 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 10 of 69 
 
1 
INTRODUCTION 
1.1 Advanced Prostate Cancer and Efficacy of Standard Androgen 
Deprivation 
Androgen deprivation therapy (ADT) has been the primary treatment for patients with advanced 
prostate cancer since the seminal recognition of the disease as androgen-dependent by Huggins and 
Hodges in 1941 [1]. Although highly effective in stabilizing disease in hormone-naïve patients, 
ADT is uniformly marked by progression to recurrent, castration-resistant disease over a period of 
18-20 months following the initiation of treatment, with an ensuing median survival of one to two 
years.  
Numerous investigators have shown that despite achieving castrate serum testosterone (T) levels, 
intraprostatic androgen levels remain substantial, at about 20-25% of the levels found in untreated 
patients [2-4]. Soft tissue metastases from patients with anorchid serum testosterone contain 
tumoral levels of T which are higher than levels in prostate tumors in eugonadal men [5]. Transcript 
levels for enzymes of androgen synthesis, including CYP17, were upregulated in the same tumors 
from 8 to 30 fold, suggesting that tumoral synthesis from cholesterol is possible.  These levels of 
testosterone and dihydrotestosterone (DHT) are well within the concentration of androgens able to 
activate the androgen receptor and to mediate proliferation and survival of prostate cancer cells. 
Therefore, ‘castrate’ levels of T and DHT are clearly capable of continuing to modulate 
intraprostatic androgen-regulated gene expression, protein synthesis, cell survival and proliferation, 
[4, 6, 7] suggesting that clinical castration defined by serum T levels cannot be equated with 
cellular castration at the tissue and genomic level.   Intratumoral androgens, including residual T, 
DHT and adrenal androgens, are implicated in nearly every mechanism whereby AR-mediated 
signaling leads to the development of castration-resistant disease [8-11]. These mechanisms 
include: 1) AR hypersensitivity due to AR gene amplification, over-expression, increased AR 
stability, or co-regulator alterations that modulate ligand sensitivity [12-14]; 2) AR mutations that 
broaden ligand specificity and confer sensitivity to adrenal androgens [15]; 3) nongenomic 
mechanisms whereby residual T and DHT modulate signaling cascades (11); and 4) tumor-specific 
dysregulation of steroid metabolic pathways effectively potentiating the intraprostatic conversion of 
adrenal androgens to T and DHT. [16-18].  
The next generation of effective agents in the treatment of prostate cancer leverage the ability to 
block tissue androgen synthesis more completely.  Abiraterone acetate is a specific CYP17 inhibitor 
with activity demonstrated against CRPC.  The proposed mechanism of action is suppression of 
androgen levels in tumor tissue as a result of suppression of testicular, adrenal and tumoral CYP17 
activity.  Clinical studies have demonstrated suppression of serum androgen levels [19] and 
xenograft studies from our group demonstrate suppression of tumor tissue androgens in preclinical 
models even in the setting of castrate serum levels [20].  Phase I and II studies have been published 
and demonstrated safety of the agent as well as efficacy of the drug in men with CRPC both before 
and after docetaxel therapy [21, 22].  These studies led to the definitive phase III registration study, 
COU-AA-301 in men with metastatic CRPC.  In this study, 1195 men with CRPC previously 
treated with docetaxel based chemotherapy were randomized to abiraterone acetate with prednisone 
or prednisone alone [23].  The study demonstrated a 3.9 month median survival advantage, with a 
hazard ratio of 0.65, favoring abiraterone acetate therapy.  Systemic effects attributable to 
abiraterone acetate were primarily related to increased mineralocorticoid levels (hypertension, 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 11 of 69 
 
hypokalemia, edema).  The improvement in relative risk of death is better than other drugs used in 
the treatment of advanced disease and led to FDA approval of abiraterone acetate for the treatment 
of metastatic, CRPC in patients treated with docetaxel.  Abiraterone acetate is an effective 
hormonal therapy which directly targets steroidogenesis and suppresses serum hormone levels 
while improving survival.  As the first in a new generation of agents targeting androgen receptor 
signaling, critical questions remain to be answered regarding mechanisms of effect in tissue and 
relevant mechanisms of de novo and acquired resistance. 
Previous work cited above demonstrated that despite the ability of standard androgen deprivation to 
suppress serum androgens, there is limited effect on tissue androgens and resistance is associated 
with augmented signaling through the androgen receptor [5, 13, 24].  Our group has performed 
detailed analysis of the effects of abiraterone acetate in two human CRPC xenografts grown in 
castrate murine hosts.  These studies demonstrate that; 1) Abiraterone acetate suppresses tissue 
hormone levels and improves survival in two human prostate cancer xenografts, in an animal model 
lacking adrenal androgens; 2) Exposure to abiraterone acetate induced upregulation of both wild 
type androgen receptor (AR) and oncogenic splice variant AR’s lacking ligand binding domain.  
These data suggest that abiraterone acetate suppresses de novo androgen synthesis by tumor and 
that resistance to abiraterone acetate therapy is mediated by upregulation of AR in an attempt to 
bypass the decrease in tissue androgens.  In addition, a subset of tumors recurred with elevated 
tissue androgen and CYP17 levels, suggesting breakthrough of CYP17 inhibition.  These 
mechanisms of resistance would provide potentially important points of inflection for either 
preventing or treating abiraterone acetate resistance in human tumors.  There have been no studies 
evaluating abiraterone acetate effect on tumor tissue from patients.  This study is designed to 
evaluate abiraterone acetate effect on tissue androgen levels in metastases from patients with 
metastatic CRPC, while evaluating tumoral AR and androgens over the course of treatment as a 
potential point of inflection for determining optimal combinations and sequential therapy.  Dose 
escalation will be explored to determine if 1000 mg twice daily will improve tumor control.  Those 
studies noted above show that there is no additional toxicity at 2000 mg daily compared to the 
standard dosing of 1000 mg daily and the lower dose was used because there was serum androgens 
were equally suppressed and there was no clear improvement in initial response in the phase I 
cohorts in patients who had never been treated with abiraterone acetate. Induction of abiraterone 
metabolism resulting in suboptimal pharmacokinetics and pharmacodynamic effect on tumor is an 
additional potential mechanism of secondary resistance to abiraterone therapy.  There is limited 
data available regarding abiraterone pharmacokinetics after prolonged dosing of abiraterone and 
there is evidence that ability of other, less effective CYP17 inhibitors such as ketoconazole, to 
suppress androgen levels wanes with time due either to incomplete CYP17 block or altered 
pharmacokinetics [31, 32].  The addition of formal pharmacokinetic evaluations before and after 
dose escalation would provide important information about secondary resistance to abiraterone 
therapy.     
1.2 Abiraterone acetate (JNJ212082) 
Abiraterone acetate is a steroidal irreversible inhibitor of CYP17 (17α hydroxylase/C17,20-lyase), 
blocking 2 important enzymatic activities in the synthesis of testosterone (Figure 1), based on the 
observation that nonsteroidal 3 pyridyl esters improved selectivity for inhibition of 17α-
hydroxylase/C17,20 lyase.  Abiraterone acetate is a potent inhibitor with an apparent inhibition 
constant of 0.5 nM.  In patients with castration resistant prostate cancer which was chemotherapy 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 12 of 69 
 
naïve, PSA response rates were 65%, and in those with previously treated with docetaxel, the PSA 
response rate was 50% with an objective response rate of 22% [25].  These response rates are 
significantly better than any agent in chemotherapy naïve or pretreated patients. Pharmacodynamic 
studies demonstrated that its effects on adrenal steroid synthesis were consistent with its mechanism 
of action.  Antitumor effects were evident with PSA response and durable objective responses using 
Response Evaluation Criteria in Solid Tumors (RECIST) criteria [26].   In the initial phase I study 
there were no grade 3 or 4 toxicities reported.  In a heavily pretreated patient population who had 
received prior docetaxel, the incidence of grade 3 and 4 toxicity was 25%, with 4 % grade 4 
toxicity.  The grade 4 toxicities were a single episode of pneumonia and a second malignancy.  
Thee adverse events from two phase III studies, study 1 (COU-301) and study 2 (COU-302) were 
as follows 
 
 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 13 of 69 
 
 
 
Abiraterone may cause fetal harm when administered to a pregnant woman. Abiraterone is 
contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if 
the patient becomes pregnant while taking this drug the patient should be apprised of the potential 
hazard to the fetus.  Women who are pregnant or women who may be pregnant should not handle 
abiraterone without protection, e.g., gloves.  Patients should also be informed that it is not known 
whether abiraterone or its metabolites are present in semen and they should use a condom if having sex 
with a pregnant woman. The patient should use a condom and another effective method of birth control 
if he is having sex with a woman of child-bearing potential. These measures are required during and for 
one week after treatment with abiraterone. 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 14 of 69 
 
1.2.1 Dosing Rationale 
The dose of abiraterone acetate to be used in this study is 1000 mg daily based on results of the 
phase III study, COU-AA-301.  In the first Phase 1 study with capsule formulation (COU-
AA-001) [26], abiraterone acetate was evaluated for safety, pharmacokinetics, and its effects on 
adrenal steroid synthesis at dose levels ranging from 250 mg to 2000 mg. Consistent with 
abiraterone acetate’s mechanism of action, hypertension (HTN), hypokalemia, and edema were 
the most commonly-observed drug-related adverse events, which were manageable with 
medication.  Adrenal metabolite analysis showed inhibition of CPY17 even at low doses of 
abiraterone acetate and a compensatory increase of corticosterone and deoxycorticosterone.  
Analysis showed that abiraterone acetate was well tolerated at all dose levels, including 2000 
mg daily, with no grade 3 or greater toxicity at 2000 mg daily.  There were no hospital 
admissions related to study drug or any evidence of clinically significant adrenal insufficiency.   
Pharmacokinetic (PK) studies showed increased systemic drug exposure at higher doses.   
Responses to abiraterone acetate were seen at similar rates for all doses of drug which 
substantially suppressed serum androgen levels.  Because no clear difference in response in 
these chemotherapy and abiraterone acetate naïve patients was discernible at higher doses, 
further dose escalation was stopped beyond 2000 mg daily and the 1000 mg daily dose was used 
as there was no clear additional effect on serum androgen levels. Higher dose levels have not 
been tested in patients with tumor progression while receiving abiraterone acetate. The potential 
that tumors in patients might escape abiraterone acetate effect by upregulating CYP17, as 
demonstrated in our recently published data in preclinical models (section 1.1), provides 
rationale for increasing dose in the event of tumor progression.   
1.2.2 Concurrent Prednisone  
In ongoing studies, patients receiving abiraterone acetate are being treated concurrently with 
glucocorticoids, including prednisone. Based on the mechanism of abiraterone acetate action 
and observations in patients with congenital deficiency of CYP17, it was anticipated that a state 
of mineralocorticoid excess could occur after pharmacologic inhibition of CYP17. Resulting 
reduced cortisol levels may lead to a compensatory ACTH surge thereby resulting in 
hypertension, hypokalemia, and fluid retention.  Notably, patients with the rare syndrome of 
congenital CYP17 deficiency do not develop adrenocortical insufficiency as corticosterone 
synthesis is unaffected.  However, as corticosterone is a weaker glucocorticoid than cortisol, 
interruption of negative feedback control of adrenocorticotrophic hormone (ACTH) occurs, 
resulting in high levels of ACTH and steroid precursors upstream of CYP17 [27].  As expected, 
when abiraterone acetate was used as a single agent in Phase 1 and 2 studies, hypertension, 
hypokalemia, and fluid retention were observed and were primarily CTC grade 1-2 in severity.  
These side effects were readily managed with potassium supplementation, eplerenone (selective 
mineralocorticoid antagonist), antihypertensive agents, and low dose corticosteroids.  Grade 1-2 
fatigue was observed in some patients and was associated with discontinuation of 
corticosteroids as required per Phase 2 protocol entry criteria and extended duration of treatment 
with abiraterone acetate.  Although there was no evidence of a dose-response relationship, 
administration of low dose corticosteroids as specified in the study improved symptoms of 
fatigue and tolerability of abiraterone acetate, including symptoms of mineralocorticosteroid 
excess.  The improved tolerability of abiraterone acetate after concomitant administration of 
low-dose corticosteroids was associated with suppression of ACTH surge and upstream adrenal 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 15 of 69 
 
steroids, suggesting that this combination may be a better tolerated and safer regimen in this 
older and frail patient population.  Prednisone was selected over other corticosteroids because it 
is commonly used as standard of care in combination with approved chemotherapy agents. The 
regimen of abiraterone acetate 1000 mg daily and low dose prednisone 5-mg twice daily, as 
tested in the phase III study has been chosen for subjects in this study.  When dose of 
abiraterone is escalated to 1000 mg twice daily, the dose of prednisone will be maintained at 5 
mg twice daily.  The primary reason for maintaining the dose of prednisone is that in phase I 
with higher dose abiraterone, there was no increase in the risk of adverse events related to 
increased mineralocorticoids or decreased cortisol.  Adrenal insufficiency is not seen as a result 
of increased corticosterone levels with CYP17  blockade, which will be unchanged with higher 
dose abiraterone. . 
1.3 Rationale for Study Design  
The studies cited demonstrate that the androgen axis remains the most important determinant of 
progression and probably the most important target to prevent progression of prostate cancer.  
Moreover, the evidence suggests that current treatment strategies lack optimal efficacy in achieving 
androgen ablation and tumor cell apoptosis, and that the adequacy of interrupting the AR pathway 
cannot be determined from serum androgen levels, but must be ascertained at the tissue and 
molecular level [4, 5]. The hypothesis of this study is that abiraterone acetate achieves more 
effective tumor control through suppression of adrenal and tumoral androgen production and will 
result in lower intratumoral levels of DHT and testosterone.  Confirming tissue suppression of 
tumor androgens is critical as the limited ability of standard LHRH agonist therapy to suppress 
tissue androgens has only recently been recognized more than 60 years after the treatment was 
described.  Similarly, delineating whether tissue based mechanisms of ligand production or receptor 
regulation are operative at resistance is critical to designing more effective therapy.  Tissue 
androgen levels and components of the AR signaling axis can only be assessed from tumor tissue.  
All patients in the current study will undergo pretreatment biopsy of metastasis amenable to biopsy, 
including bone, node or soft tissue.  The Genitourinary oncology group has participated in multiple 
studies which require pretreatment tumor biopsy using CT guided tissue acquisition, with 
successful tissue acquisition in 70% of the biopsy sessions.   Patients unable to undergo metastasis 
biopsy may undergo biopsy of primary prostate instead, as resistant primary prostate cancer also 
upregulates androgens.  The standard operating procedure for tissue acquisition and processing is 
contained in the separate lab manual (Tissue Acquisition and Processing). Tissue from the six core 
biopsies will be collected and analyzed for tissue DHT, testosterone, DHEA and androstenedione, 
as well as AR and AR splice variants. These assays are well established within our group [5, 28, 
29].  Serum androgens drawn at the same time intervals will be compared with the tissue androgens 
measured above. Three cohorts of patients will be treated with LHRH agonist or orchiectomy, 
Abiraterone acetate 1000 mg daily and prednisone 5 mg twice daily in order to allow evaluation of 
tissue androgens and mechanisms of resistance to abiraterone acetate. The total cohort size will be 
10 patients per cohort with successful acquisition of tumor at initial biopsy.  Repeat biopsy will be 
performed at 4 weeks (cohort 1), 12 weeks (cohort 2) or at progression as defined by radiographic 
progression (cohort 3).  We will sequentially assign patients to repeat biopsy at 4 weeks or 12 
weeks until both cohorts are complete.  Patients who progress prior to planned biopsy will be 
considered part of cohort 3 and undergo biopsy at progression.  Once cohorts 1 and 2 are full, all 
patients will be assigned to cohort 3. All patients will be offered elective participation in evaluation 
of pharmacokinetics at progression at 1000 mg daily.  For patients in all cohorts, there will be the 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 16 of 69 
 
option of dose escalation of abiraterone acetate to 1000 mg twice daily. In the phase I studies cited, 
there were no grade 3 or 4 toxicities seen at 2000 mg daily. The rationale for dose escalation to 
1000 mg twice daily compared to 2000 mg once daily is that previous data indicated that there was 
minimal increase in abiraterone PK exposure when the dose increased from 1000 mg QD to 2000 
mg QD. Given the poor solubility of abiraterone acetate, this less than dose proportional increase in 
PK exposure was most likely caused by solubility-limited absorption. Administering the total daily 
dose (2000 mg per day) in two divided doses (1000 mg BID) may help circumvent this issue by 
increasing the soluble fraction of abiraterone acetate thereby enhancing overall absorption.  Dose 
escalation will test the hypothesis generated from preclinical studies that more effective CYP17 
inhibition may provide additional benefit in the face of tumor progression.   
2 
STUDY OBJECTIVES 
2.1 Primary Objective  
The primary objective of this study is; 
To determine the magnitude of tissue testosterone suppression by abiraterone acetate in metastatic 
CRPC (resistant to LHRH agonist or orchiectomy ± antiandrogen) after one month of treatment to 
establish tissue based mechanism of action. 
2.2 Exploratory Objectives 
The exploratory objectives of this study are: 
 
To determine the ability of abiraterone acetate to suppress tumor testosterone after 12 weeks 
of treatment. 
 To determine tissue testosterone from metastasis at time of progression during abiraterone 
acetate treatment.  
 To determine response to dose escalation of abiraterone acetate at clinical progression   
 To determine potential mechanisms of resistance to abiraterone acetate by analyzing 
pharmacokinetics at clinical progression, tissue androgen levels at baseline and at radiographic 
progression, evaluating wild type and splice variant AR levels at baseline and at time of 
progression and cDNA microarray at progression 
 To determine if microRNA acquired from peripheral blood reflect molecular changes in tumor 
metastases and are a potential biomarker for mechanisms of sensitivity and resistance. 
 To evaluate pharmacokinetics of dose escalated abiraterone at 1000 mg twice daily 
3 
INVESTIGATIONAL PLAN 
3.1 Overall Study Design and Plan 
This is an open-label study with 30 patients with metastatic prostate cancer resistant to LHRH 
agonist, or orchiectomy ± antiandrogen.  All patients will be treated with continued Lupron (or have 
prior orchiectomy), and abiraterone acetate with prednisone as therapy during study enrolled from 1 
study center.   This is a study assessing the primary endpoint of suppression of tissue androgens at 4 
weeks,   After informed consent, all patients will undergo successful biopsy of a metastatic lesion 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 17 of 69 
 
and then be enrolled alternating between the first cohort of patients undergoing repeat biopsy at 4 
weeks (cohort 1), or repeat biopsy at 12 weeks (cohort 2) until 10 patients are in each cohort.  If any 
patients experience progression prior to planned biopsy they will be included in cohort 3 (biopsy at 
progression) and the patient will be replaced in cohort 1 or 2.  After cohorts 1 and 2 have been 
filled, patients will be assigned to cohort 3, with all patients undergoing biopsy at the time of 
progression, with a total of 10 patients enrolled in cohort 3 cohort. At the time of progression, 
patients may have pharmacokinetics performed at the dose of 1000 mg daily (elective study).  All 
patients will have the dose of abiraterone acetate escalated to 1000 mg twice daily. Repeat 
pharmacokinetics at the higher dose will be performed 7-14 days after dose escalation (elective). 
All patients in all cohorts will be treated to clinical or radiographic progression, or until another 
intervening reason for withdrawal from study (Section 6.9). 
3.1.1 Primary Endpoint 
The primary efficacy endpoint (testosterone) will be assayed from the tumor biopsy procured at 
baseline, and at approximately Week 4.  Tissue androgen measurements will be performed by 
the Nelson and Mostaghel laboratories at Fred Hutchinson Cancer Research Center using 
previously published techniques.  Assumptions regarding basal tissue androgens and androgens 
after abiraterone acetate treatment at response and progression are derived from xenograft 
studies of abiraterone acetate effect in castrate male mice. Baseline tissue testosterone in 
untreated CRPC xenografts is 0.687 ± 0.364 pg/mg, approximating that seen in human CRPC 
metastases.  Nadir tissue testosterone at 7 and 21 days is 0.027 ± 0.009 pg/mg (approximating 
one and three month levels) which rise to 0.222 ± 0.246 pg/mg at progression. 
3.1.2 Exploratory Endpoints 
 To determine the ability of abiraterone acetate to suppress tumor testosterone after 12 weeks 
of treatment. 
 To determine tissue testosterone from metastasis at time of progression during abiraterone 
acetate treatment.  
 To determine PSA response to dose escalation of abiraterone acetate (PSA response by 
PCWG2 criteria) and associate response to tumor androgen levels prior to dose escalation   
 To determine potential mechanisms of resistance to abiraterone acetate by analyzing tissue 
androgen levels at baseline and at progression, evaluating wild type and splice variant AR 
levels at baseline and at time of progression, pharmacokinetics at progression and cDNA 
microarray at progression 
 To determine if microRNA acquired from peripheral blood reflect molecular changes in 
tumor metastases and are a potential biomarker for mechanisms of sensitivity and resistance. 
 To evaluate pharmacokinetics of dose escalated abiraterone at 1000 mg twice daily 
1. Tissue and serum testosterone, DHT, androstenedione and DHEA will be analyzed from 
collection at baseline, at approximately weeks 4, 12 and progression ) in the different cohorts 
of patients as described. This will address the exploratory objects assaying the various 
androgens at defined time points and progression.   
2. Response to dose escalation will be defined as PSA and RECIST response.  
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 18 of 69 
 
 PSA response as defined as decline from the PSA at initiation of therapy and then with 
dose escalation of abiraterone acetate will be evaluated per PCWG2 criteria.  This will be 
determined by PSA’s performed at monthly intervals.  The subsequent response to dose 
escalation (if any) will be correlated with tumor androgens.   
 RECIST - participants with measurable disease will be assessed by RECIST (1.1), bone 
scan and PSA criteria. For the purposes of this study, participants should be re-evaluated 
every 4 weeks by PSA and every 12 week with CT and bone scan. PCWG2 
recommendations for response and progression definitions will be followed for PSA 
progression and RECIST criteria for progression on imaging.  Patients should not be 
taken off treatment for PSA progression alone but should remain on treatment until 
documented progression by imaging 
3. Mechanisms of resistance will be evaluated by assaying; 
 Tissue androgens – as described above 
 AR levels – tumor tissue will be evaluated by RT-PCR for wild type and splice variant 
(AResdel567 and ARv7) at initiation of therapy, 4 weeks, 12 weeks and progression. 
 cDNA microarray – microdissected tumor from biopsies taken at progression will be 
processed and analyzed as previously described  in order to identify signaling pathways 
relevant in progression (Risk, Clin Cancer Res. 2010 16:5414-23.) 
 Pharmacokinetics – plasma samples drawn as described at progression and after dose 
escalation will be analyzed by liquid chromatography followed by tandem mass 
spectrometry (LC-MS/MS) with subsequent calculation of Cmax, Tmax, and AUC(0-24) 
 
4. MicroRNA analysis - Plasma will be collected for miRNA analysis by the Tewari lab, Fred 
Hutchinson Cancer Research Center.  In these analyses a panel of miRNA’s will be assessed 
at baseline, 4 weeks, 12 weeks and progression in the cohorts undergoing biopsy at these 
time points. Plasma samples will be profiled for the relative abundance of 375 miRNAs by 
using miRNA Ready-to-Use PCR, Human Panel I, V2.M qRT-PCR arrays.  Candidate 
miRNA strongly associated with response or progression will be quantitated in biopsy tissue 
as possible.   
4 
STUDY POPULATION SELECTION 
4.1 Study Population 
Patients for the study will be recruited from within the Seattle Cancer Care Alliance (SCCA) and 
University of Washington, which are separate practice sites within the same practice and share a 
single IRB. Patients will be identified by their oncologist as eligible for the study and the study will 
be discussed with the patient by the provider.  If patients are interested in participating, they will be 
counseled and informed consent will be obtained by one of the investigators.  A total of 30 subjects 
will be enrolled into the study, with consideration that additional patients may be enrolled in order 
to acquire 30 sets of informative biopsies. 
4.2 Inclusion Criteria 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 19 of 69 
 
Each patient must meet the following criteria to be enrolled in this study. 
1. 
Have signed an informed consent document indicating that the subjects understands the 
purpose of and procedures required for the study and are willing to participate in the study  
2. 
Written Authorization for Use and Release of Health and Research Study Information has 
been obtained 
3. 
Be willing/able to adhere to the prohibitions and restrictions specified in this protocol 
4. 
Male aged 18 years and above 
5. 
Able to swallow the study drug whole as a tablet 
6. 
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.  
7. 
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 and sponsor during the study and for 1 week after last dose of abiraterone 
acetate 
8. 
Histologically proven adenocarcinoma of the prostate. 
9. 
ECOG performance status <2  
10. Metastatic castration resistant prostate cancer as defined by serum testosterone < 50 ng/ml 
and one of the following: 
a. PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions at 
least 1 week apart. 
b. Evaluable disease progression by modified RECIST (Response Evaluation 
Criteria in Solid Tumors)  
c. Progression of metastatic bone disease on bone scan with > 2 new lesions 
11. Maintenance of Lupron or antagonist unless previously treated with orchiectomy. 
12. The presence of metastatic disease amenable to CT or ultrasound guided biopsy. This may 
include thoracolumbar vertebral bodies, pelvis, femur or humerus, or soft tissue or nodal 
metastasis amenable to biopsy (excluding lung or pleural lesions).  
13. Patients may have received secondary hormonal manipulations (excluding prior Abiraterone 
acetate, MDV3100 or TAK700) or up to two lines of chemotherapy.  All prior therapy 
except Lupron must have been discontinued for more than 4 weeks before enrollment.  
14. Baseline laboratory values must be as follows: 
 Serum potassium of ≥ 3.5 mEq/L 
 Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin 
levels < 1.5 x ULN 
 Serum albumin of ≥ 3.0 g/dL 
 Total bilirubin ≤ 1.5 x ULN 
 Calculated creatinine clearance ≥ 60 mL/min 
 Platelet count of ≥ 100,000/μL 
 Absolute neutrophil count of > 1500 cell/mm3 
 Hemoglobin of ≥ 9.0 g/dL 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 20 of 69 
 
4.3 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. Active infection or other medical condition that would make prednisone/prednisolone 
(corticosteroid) use contraindicated 
2. Patients who are currently receiving active therapy for other neoplastic disorders will not be 
eligible. 
3. Patients with histologic evidence of small cell carcinoma of the prostate will not be eligible. 
4. Known brain metastasis 
5. 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 
6. Active or symptomatic viral hepatitis or chronic liver disease 
7. History of pituitary or adrenal dysfunction 
8. 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 II-IV heart disease or cardiac ejection fraction measurement of < 
50 % at baseline 
9. Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy 
10. Administration of an investigational therapeutic within 30 days of screening. 
11. Patients with dementia/psychiatric illness/social situations that would limit compliance with 
study requirements or would prohibit the understanding and/or giving of informed consent 
will not be eligible 
12. Patients with any condition that, in the opinion of the investigator, would compromise the 
well-being of the subject or the study or prevent the subject from meeting or performing 
study requirements 
13. Patients requiring therapeutic anticoagulation (e.g., warfarin, Dabigatran, heparin, or low 
molecular weight heparins (Lovenox, dalteparin))    
14. Patients with poorly controlled diabetes 
15. Patients with a history of gastrointestinal disorders (medical disorders or extensive surgery) 
that may interfere with the absorption of the study agents 
16. Patients with a pre-existing condition that warrants long-term corticosteroid use in excess of 
study dose 
17. Patients with known allergies, hypersensitivity, or intolerance to abiraterone acetate or 
prednisone or their excipients. 
18. Child-Pugh class B or C hepatic impairment 
5 
STUDY TREATMENT(S) 
5.1 Description of Treatment(s) 
5.1.1 Abiraterone acetate 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 21 of 69 
 
Abiraterone acetate is an oral, selective, steroidal inhibitor of the steroidogenic cytochrome 
CYP17 that serves as an androgen antagonist. Abiraterone acetate has been evaluated in two 
phase III, randomized, placebo controlled studies. The first study treated 1195 patients who had 
previously received docetaxel (COU-301). This study showed that abiraterone acetate improved 
overall survival by 4 months compared to prednisone alone with a hazard ratio of 0.65 for 
patients receiving abiraterone acetate. The secondary endpoints of PSA response and time to 
progression also favored abiraterone acetate.  Based on this study abiraterone acetate was 
approved for use in men with metastatic, CRPC after prior docetaxel therapy. The second study 
treated 1088 patients with metastatic castration-resistant prostate cancer who had not received 
previous chemotherapy.(COU-302). This study showed that abiraterone acetate improved 
radiographic progression free survival compared to prednisone alone with a hazard ratio of 0.53 
for patients receiving abiraterone acetate. Based on this study abiraterone acetate was approved 
for use in men with metastatic, CRPC prior to docetaxel therapy.  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 during tableting). Abiraterone 
acetate for this study will be provided by Janssen Services.  
5.1.2 Prednisone 
Prednisone is a corticosteroid.  It is used in the study to suppress the compensatory increase in 
mineralocorticoid which occurs after CYP17 inhibition.  Prednisone is supplied as a 5 mg tablet.  
Commercial supplies of prednisone will be used for this trial. 
5.2 Treatments Administered 
5.2.1 Abiraterone acetate 
Starting on study Day 1, patients will be instructed to take 1000mg administered orally once 
daily in combination with prednisone 5 mg administered orally twice daily. 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 was administered with a meal 
compared to a fasted state. The safety of these increased exposures when multiple doses of 
abiraterone  are taken with food has not been assessed.  Treatment will continue until there is 
evidence of clinical or radiologic progression or intolerance to drug (Grade 3 or 4). . Patient 
compliance will be tracked through interview and pill count at study visit.  If an abiraterone 
acetate dose is missed, it should be omitted and will not be made up. If dosing compliance is not 
100% in the absence of toxicity, patient should be re-instructed regarding proper dosing 
procedures and continue in the protocol. After progression by radiographic or clinical criteria 
patients in all cohorts are eligible to have the dose of abiraterone escalated to 1000 mg twice 
daily taken in the same manner.  
5.2.2 Prednisone 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 22 of 69 
 
Starting on study Day 1, patients will be instructed to take 5-mg prednisone PO twice daily.  
Treatment duration of prednisone will be for the duration of study concurrent with abiraterone 
acetate. In the abiraterone acetate dose escalation cohort at progression, prednisone dose will 
not be changed. At discontinuation of study, after abiraterone acetate is discontinued, 
prednisone will be decreased to 5 mg every other day for one week and then discontinued. If a 
prednisone dose is missed, it should be omitted and will not be made up.  
Although not considered a study agent, subjects will also receive their regularly prescribed 
Leuprolide (to be administered as prescribed). If patients have undergone orchiectomy, use of 
Leuprolide is not necessary. 
5.3 Concomitant Therapy 
Concurrent treatment with Leuprolide is mandatory at screening and must be continued unless the 
subject has undergone orchiectomy. 
The use of any concurrent drug from screening and while on study (other than those listed in 
Section 5.2), prescription or over-the-counter, is to be recorded on the patient's CRF along with the 
reason the drug was taken.   
Concurrent enrollment in another clinical investigational drug or device study is prohibited. 
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 and in such cases, the use of steroids will be documented 
as concomitant drug 
 If the permissibility of a specific drug/treatment is in question, please contact the study 
investigator-sponsor. 
5.4 Restrictions 
The concurrent administration of other anticancer therapy, including cytotoxic or hormonal agents 
(except LHRH agonists), or immunotherapy, is prohibited therapy.  Use of other investigational 
drug therapy for any reason is prohibited.  The decision to administer a prohibited drug/treatment 
will be made by the investigator based on the consideration of the safety of study participant. 
5.5 Potential for Drug-Drug Interactions 
Effects of Abiraterone on Drug Metabolizing Enzymes 
Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a 
CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) 
were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone 
acetate 1000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 23 of 69 
 
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 
1,000mg abiraterone acetate. Therefore, patient should be monitored closely for signs of toxicity 
related to CYP2C8 substrate with a narrow therapeutic index if used concomitantly with Zytiga.  
 
Drugs that Inhibit or Induce CYP3A4 Enzymes 
In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 
inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1000 
mg, the mean plasma AUC∞ of abiraterone was decreased by 55%.  Strong inducers of CYP3A4 
(e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during treatment 
with ZYTIGA are to be avoided, or used with careful evaluation of clinical efficacy.  
In a separate clinical pharmacokinetic interaction study of healthy subjects, coadministration of 
ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the 
pharmacokinetics of abiraterone.  
 
5.6 Treatment Compliance 
A dosing compliance check will be conducted at each study visit while subject is taking abiraterone 
acetate.  If a patient misses 14 or more doses within a single 28-day cycle, the patient should be 
discontinued from the study treatment Phase.  All End-of-Study treatment procedures should be 
followed.  The patient will be followed for PSA progression. 
A current and accurate account of the number of investigational tablets will be maintained including 
the amount of investigational tablets received by the investigator, amount dispensed each patient, 
the number of units returned to the investigator by each patient, and the number of units destroyed 
on site, after full reconciliation at the completion of the study.  A detailed inventory must be 
completed and maintained for the study treatment.   
5.7 Packaging and Labeling 
Abiraterone acetate tablets will be provided to the site with marketing packaging and labeling.  
Tablets will be packaged for dispensing 4-week supplies of 250 mg tablets on a per patient basis.  
Patients will be provided with no more than a 4-week supply of abiraterone acetate at any one time. 
Lupron and prednisone will be provided or prescribed to each patient in accordance with this 
protocol and under the guidelines of the site or pharmacy’s dispensation standard operating 
procedure.  
5.8 Storage  
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 24 of 69 
 
5.8.1 Pharmacy Storage Requirements  
Study medication must be stored in a secure area and administered only to patients entered into 
the clinical study in accordance with the conditions specified in this protocol. 
Bottles of abiraterone acetate should be stored at a room temperature between 20oC to 25oC 
(68oF to 77oF); excursions permitted to 15oC to 30oC (59oF to 86°F) with the cap on tightly and 
should not be refrigerated. Additional information is provided in the abiraterone acetate 
Investigator’s Brochure or US prescribing information (www.zytiga.com). 
Lupron and prednisone should be stored according to manufacturer instructions as indicated on 
the commercial packaging. 
5.8.2 Storage Requirements For The Patient 
Bottles of abiraterone acetate should be stored at room temperature between 20oC to 25oC (68oF 
to 77oF) with the cap on tightly and should not be refrigerated.  Patients should be advised to 
keep all medications out of the reach and out of sight of children. Based on its mechanism of 
action, abiraterone acetate may harm a developing fetus. Therefore, women who are pregnant or 
women who may become pregnant should not handle abiraterone acetate without protection, 
e.g. gloves. 
Patients should store prednisone according to manufacturer instructions as indicated on the 
commercial packaging. 
5.9 Handling abiraterone acetate tablets 
This medicine may cause harm to the unborn child if taken by women who are pregnant.  It 
should not be taken by women who are breast-feeding.  Women who are pregnant or who may 
be pregnant should wear gloves if they need to touch abiraterone acetate tablets.  Study staff and 
caregivers should be notified of this information, to ensure the appropriate precautions are 
taken. 
5.10 Investigational Product Retention and Accountability at Study Site 
At the time of delivery of study treatment to the site, the investigator, designee, or Pharmacist 
(where appropriate) will sign a drug receipt form to confirm that the supplies for the study have 
been received.  This form will specify supply, lot numbers, quantities shipped/delivered, and date of 
receipt.  The form will also contain statements confirming that the study treatment has been 
received in good condition. 
Study treatment must be stored in a secure location.  Accountability for study treatment is the 
responsibility of the investigator.   
Study treatment must only be dispensed by a Pharmacist or medically qualified staff (research 
coordinator).  Study treatment is to be dispensed only to patients enrolled in this study.  Once the 
study treatment is prepared for a patient, it can only be administered to that patient.  
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 25 of 69 
 
The study site must maintain accurate records demonstrating dates and amount of study treatment 
(abiraterone acetate, Lupron, and prednisone) received, to whom dispensed (patient by patient 
accounting), and accounts of any study treatment accidentally or deliberately destroyed.  At the end 
of the study, reconciliation must be made between the amount of study treatment supplied, 
dispensed, and subsequently destroyed. No abiraterone acetate tablets or containers will be 
destroyed without prior written approval from Janssen.  Study site staff should refer to information 
located in Investigator’s Brochure for specific instructions on the handling, storage, and 
administration of the study drug. 
6 
STUDY PROCEDURES 
6.1 Informed Consent 
Written Informed Consent and Authorization must be obtained from the patient in accordance with 
local practice and regulations. The study will be discussed with the patient, and a patient wishing to 
participate must give written informed consent and Authorization for Use and Release of Health 
and Research Study Information prior to any study-related procedures or change in treatment.   
A signed, Institutional Review Board/Ethics Committee (IRB) approved, informed consent must be 
obtained from patients before any study specific procedures can occur.  Confirmation of the 
patient’s informed consent and the informed consent process must also be documented in the 
patient’s medical record. 
A copy of the fully signed informed consents will be given to the patient. 
All patients who sign informed consent will be assigned a study number, in the order enrolled.  
Format will be the CC-IRB number (7639), patient number (001, 002, 003 …), patient initials:  
7639-001-FML.  Initials will be included in the case report forms, but will not be marked on blood 
or tissue samples.  
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.  If 
it is not possible to use the same evaluator to follow the patient, then evaluations should overlap 
(i.e., examine the patient together and discuss findings) for at least one visit. 
Physical examination includes HEENT (head, eyes, ears, nose, and throat), chest, cardiac, 
abdominal, extremities, neurologic, and lymph node examinations.  
Vital signs include blood pressure, heart rate. Weight will be recorded at every visit. Height will be 
recorded at screening visit only. 
6.4 Clinical Laboratory Tests 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 26 of 69 
 
6.4.1 Laboratory Parameters 
Clinical laboratory tests will include the following: 
Hematology: 
- Hematocrit (Hct) 
- Hemoglobin (Hgb) 
- Platelet count with differential 
- Red blood cell (RBC) count  
- White blood cell (WBC) count 
with differential  
 
Additional laboratory tests: 
- Prostate specific antigen (PSA)  
- Serum drawn for hormone 
measurements 
Serum Chemistry: 
- Albumin (ALB) 
- Blood urea nitrogen (BUN) 
- Calcium (Ca) 
- Carbon dioxide (CO2) 
- Chloride (Cl) 
- Creatinine 
- Glucose 
- Magnesium 
- Potassium (K) 
- Sodium (Na) 
Liver Functions 
- Alanine aminotransferase (ALT; 
SGPT) 
- Aspartate 
aminotransferase 
(AST; SGOT) 
- Alkaline phosphatase (ALK-P) 
- Total bilirubin 
 
6.4.2 Sample Collection, Storage, and Shipping 
The institutional laboratories at Seattle Cancer Care Alliance and University of Washington will 
analyze all hematology, blood chemistry, and PSA samples collected for the study.  Samples 
will be analyzed at a facility meeting Good Laboratory Practice (GLP) requirements and/or 
using methods documented in a methods validation report.  Samples for hormones other than 
testosterone will be processed at University of Washington in the Mostaghel laboratory. 
6.4.2.1 Biopsy acquisition and tissue handling 
Please see the attached laboratory manual for detailed instructions regarding acquisition 
and handling of tissue specimens.  In brief, CT guided biopsy of a bone or soft tissue 
lesion (pelvic nodes) or core needle aspirate of superficial nodal tissue (supraclavicular or 
cervical nodes) will be performed by an interventional radiologist or pain physician after 
evaluation of bone scan and CT scan.   
On the day of biopsy, prior to the procedure, 20 ml of blood will be drawn for serum and 
plasma.  Aspirin and other medications containing aspirin (e.g. Plavix, Aggrenox) should 
be discontinued 7 days prior to the biopsy.  Patients requiring other anticoagulant therapy 
(coumadin, lovenox, pradaxa, etc.) are not eligible.  Blood samples will be drawn as 
clinically indicated to document an acceptable coagulation profile (INR < 1.5, PTT < 45, 
platelets >50,000).   
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 27 of 69 
 
On the day of the biopsy, a short physical exam will be performed by the radiologist 
including assessing the patient’s general ASA score and airway rating.  Informed written 
consent will be obtained following discussion of the risks (bleeding, infection, adjacent 
tissue injury, and pain) and benefits of the procedure.  Biopsies will be performed under 
CT- or ultrasound guidance without the administration of intravenous contrast.   
RADI Bonopty 15 g needles [1.7 mm bore] (RADI Medical Systems, Uppsala, Sweden) 
are preferred for bone lesions with an intact cortex.  Osticut or Jamshidi needles 14g may 
also be used. 
Several bone specimens (up to 6) will be obtained.  Samples will be given to a dedicated 
technician present during the procedure for sample processing.   
Conscious sedation will be administered by a trained radiology nurse using small doses 
of Versed and fentanyl titrated to the patient’s level of discomfort.  Following the biopsy, 
patients will be observed following their last dose of conscious sedation for any 
complications (severe pain, hematoma, neurologic deficit).  They will be discharged after 
fulfilling PACU discharge criteria prior to departing with a chaperone.   
6.4.2.2 Sample Labeling 
Samples will be marked with the assigned patient number, collection date and timepoint 
(e.g., BL, Wk 4, Wk 12, PD).  Because collection date is included in the Limited Data Set 
defined by HIPAA, these samples cannot be considered de-identified.  However, the link 
between patient number and patient identity are in a separate, locked room.  Non-clinical 
staff will not have access to patient identifiers beyond the sample collection date. 
6.4.2.3 Sample Storage 
Unfixed samples will be stored on-site in a -80° freezer until processing.  Fixed samples 
will be stored on-site in a temperature-controlled setting appropriate to the fixation 
medium. 
Samples will be destroyed when the research described in this protocol is complete.  
Samples will be used for only the purposes delineated in this protocol. 
 
6.5 Efficacy Assessments 
6.5.1 The Primary Endpoint Measure 
The primary efficacy endpoint (testosterone) will be assayed from the tumor biopsy procured at 
baseline, at approximately Week 4.  Tumor testosterone will be analyzed from biopsies 
collected at baseline, and at week 4.  Tissue androgen measurements will be performed by the 
Nelson and Mostaghel laboratories at Fred Hutchinson Cancer Research Center using 
previously published LC-MS/MS techniques. 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 28 of 69 
 
6.5.2 Exploratory Endpoint Measures   
The exploratory endpoint measures will address the exploratory objectives as described in 
Section 2.2.   
1. Tissue and serum testosterone, DHT, androstenedione and DHEA will be analyzed from 
collection at baseline, at week 4, week 12 (± 2 weeks) and at progression (± 2 weeks) in the 
different cohorts of patients as described.  
2. PSA response as defined as decline from the PSA at initiation of therapy and with dose 
escalation of abiraterone acetate will be evaluated per PCWG2 criteria.  This will be 
determined by PSA’s performed at monthly intervals.  The subsequent response to dose 
escalation (if any) will be correlated with tumor androgens. 
3. RECIST - participants with measurable disease will be assessed by RECIST (1.1), bone scan 
and PSA criteria. For the purposes of this study, participants should be re-evaluated every 4 
weeks by PSA and every 12 week with CT and bone scan. PCWG2 recommendations for 
response and progression definitions will be followed for PSA progression and RECIST 
criteria for progression on imaging.  Patients should not be taken off treatment for PSA 
progression alone but should remain on treatment until documented progression by imaging. 
Detailed discussion of progression and response is outlined in Appendix 5.  
4. AR levels – tumor tissue will be evaluated by RT-PCR for wild type and splice variant 
(AResdel567 and ARv7) at initiation of therapy, 4 weeks, 12 weeks and progression. 
5. Pharmacokinetics – plasma samples drawn at progression and after dose escalation will be 
analyzed by liquid chromatography followed by tandem mass spectrometry (LC-MS/MS) 
with subsequent calculation of Cmax, Tmax, and AUC(0-24) 
6. MicroRNA - Plasma will be collected for miRNA analysis by the Tewari lab, Fred 
Hutchinson Cancer Research Center.  In these analyses a panel of miRNA’s will be assessed 
at baseline, 4 weeks, 12 weeks and progression in the cohorts undergoing biopsy at these 
time points. Plasma samples will be profiled for the relative abundance of 375 miRNAs by 
using miRNA Ready-to-Use PCR, Human Panel I, V2.M qRT-PCR arrays.  Candidate 
miRNA strongly associated with response or progression will be quantitated in biopsy tissue 
as possible. 
7. cDNA microarray – microdissected tumor from biopsies taken at progression will be 
processed and analyzed as previously described  in order to identify signaling pathways 
relevant in progression (Risk, Clin Cancer Res. 2010 16:5414-23.) 
6.6 Safety Assessments 
All participants receiving investigational agents will be evaluated for safety.   The safety parameters 
include all laboratory tests and hematological abnormalities, physical examination findings, and 
spontaneous reports of adverse events reported to the investigator by participants.  All toxicities 
encountered during the study will be evaluated according to the NCI criteria specified in the 
protocol and recorded prior to each course of therapy.  Life-threatening toxicities should be reported 
immediately to the Protocol Chair and Institutional Review Board (IRB).  
Safety assessments will be carried out as delineated in Section 7.7 and will include: 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 29 of 69 
 
 Adverse events including laboratory adverse events will be graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 
 Electrocardiograms (ECGs). 
 Laboratory tests (CBC with differential, platelets, LFT’s, chemistry, and serum lipids) 
 Vital Signs (blood pressure, heart rate, respiratory rate and weight)  
 Physical exam  
 ECOG performance status 
6.7 Safety Data Collection, Recording and Reporting 
All observed or volunteered adverse events regardless of causal relationship to study drug will be 
recorded on the adverse event page(s) of the case report form (CRF). 
Please refer to Appendix 4 for Janssen Services, LLC’s “Adverse Event Reporting Requirements 
for Interventional Studies.”  Some of the information may overlap with the items below. 
6.7.1 Definition of Adverse Event (AE) 
An adverse event is defined in the International Conference on Harmonisation (ICH) Guideline 
for Good Clinical Practice as “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” (ICH E6:1.2).  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
diagnosis or disease temporally associated with the use of a medicinal product, whether or not 
related to the medicinal product.  For the purposes of this study, temporal association is defined 
as the time between the subject’s informed consent signature through 28 days after the final 
dose of abiraterone acetate.   
AEs further include worsening of a pre-existing medical condition (e.g., diabetes, migraine 
headaches, gout, hypertension, etc.) which has increased in severity, frequency or duration, or is 
associated with significantly worsened outcomes.   
The investigator or a medically licensed designee must pursue and obtain information adequate 
to determine the following:  Grade (CTCAE v4.0), Causality (relationship to abiraterone 
acetate) and Outcome.  . The investigator’s assessment of Grade, any Intervention (medication, 
procedure, etc.), Causality and Outcome will be indicated by signature of the PI or designated 
physician on the adverse event CRF.  For adverse events with a causal relationship to the 
investigational product, follow-up by the investigator is required until the event or its sequelae 
resolve or stabilize at a level acceptable to the investigator, or his/her designated representative.   
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. 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 30 of 69 
 
Special Reporting Situations (SRS)  
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 medicinal product from breastfeeding  
 suspected abuse/misuse of medicinal Johnson & Johnson product 
 inadvertent or accidental exposure to medicinal Johnson & Johnson product 
 any failure of expected pharmacological action (i.e., lack of effect) of medicinal Johnson 
& Johnson product 
 unexpected therapeutic or clinical benefit from medicinal Johnson & Johnson product  
 medication error involving medicinal 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 Johnson & Johnson 
product  
Adverse events of special interest to Janssen Services, LLC include hypokalemia, abnormal 
liver function tests (AST, ALT, bilirubin), hypertension and edema.  See Management of Study 
Drug-related Adverse Events, for clinical management of both special interest and general AEs.   
If the investigator or designee determines that an AE meets the criteria for classification as a 
Serious Adverse Event (SAE) or Suspected Unexpected Adverse Event Reporting (SUSAR), 
s/he will immediately notify the UW/FHCRC Cancer Consortium IRB, Janssen Services and 
FDA.  See Section 6.7.2 for definition of SAEs and SUSARs, and 6.7.4 for reporting guidelines. 
Interventions for pretreatment conditions (e.g., elective cosmetic surgery) or medical procedures 
that were planned before study enrollment are not considered adverse events.   
6.7.2 Definition of a Serious Adverse Event 
An adverse event or suspected adverse reaction is considered ‘‘serious’’ if, in the view of the 
investigator or a medically licensed designee, it results in any of the following outcomes:  
 Death,  
 a life-threatening adverse event,  
o Life-threatening adverse event or life-threatening suspected adverse reaction.  
 An adverse event or suspected adverse reaction is considered ‘‘life-
threatening’’ if its occurrence places the patient or subject at immediate 
risk of death.  This definition 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,  
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 31 of 69 
 
 a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
 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. 
A hospitalization meeting the definition for “serious” is any in-patient hospital admission that 
included a minimum of an overnight stay in a health care facility.  Interventions for 
pretreatment conditions (e.g., elective cosmetic surgery) or medical procedures that were 
planned before study enrollment are not considered SAE/SUSARs for the purposes of this 
study.  Inpatient admission does not include admissions to rehabilitation facilities, hospice 
facilities, skilled nursing facilities, nursing homes, routine emergency room admissions, same 
day surgery (as outpatient/same day/ambulatory procedures) or social admission (e.g., subject 
has no place to sleep). 
6.7.3 Suspected Unexpected Serious Adverse Events (SUSARS) 
Suspected Unexpected Serious Adverse Reactions (SUSARS) are events which are serious as 
per the above criteria, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure or Package Insert) and are judged by the 
investigator to be related to investigational product.   
6.7.4 Reporting Procedures for Adverse Events 
The investigator is responsible for ensuring that all non-serious adverse events (as defined in 
Section 6.71 and as further specified below) observed by the investigator or reported by subjects 
are collected and recorded in the CRF.  Source documents may include the subjects’ medical 
records, patient diaries or study-specific worksheets.  Recording for all events should be done in 
a concise manner using standard, acceptable medical terms.  New AEs occurring between the 
patient’s consent signature through 28 days after his last dose of abiraterone acetate will be 
captured.   
The adverse event recorded should not be a procedure or a clinical measurement (i.e. a 
laboratory value or vital sign) but should reflect the reason for the procedure or the diagnosis 
based on the abnormal measurement. 
Preexisting conditions that worsen in severity or frequency during the Study should also be 
recorded (a preexisting condition that does not worsen is not an adverse event).  Further, a 
procedure or surgery is not an adverse event; rather, the event leading to the procedure or 
surgery is considered an adverse event.  Any event requiring unplanned in-patient 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 32 of 69 
 
hospitalization that occurs during the course of a subject’s participation in a trial must be 
reported as an SAE, as previously stated. 
If, in the investigator’s judgment, a clinically significant worsening from baseline is observed in 
any laboratory or other test parameter (e.g. electrocardiogram (ECG), angiogram), physical 
exam finding, or vital sign, a corresponding clinical adverse event should be recorded. 
If a specific medical diagnosis has been made, that diagnosis or syndrome should be recorded as 
the adverse event, whenever possible.  However, a complete description of the signs, symptoms 
and investigations which led to the diagnosis should be provided.  For example, if clinically 
significant elevations of liver function tests are known to be secondary to hepatitis, “hepatitis” 
and not “elevated liver function tests” should be recorded.  If the cause is not known, the 
abnormal test or finding should be recorded as an adverse event, using appropriate medical 
terminology (e.g., thrombocytopenia, peripheral edema, QT prolongation). 
For all adverse events, sufficient information should be obtained by the investigator to 
determine the causality of the adverse event (e.g., study drug, other illness, progressive 
malignancy, etc.).  The relationship of the adverse event to the investigational product will be 
assessed by means of the question, “Is there a reasonable possibility that the event may have 
been caused by the investigational product?”  The investigator should respond to this question 
with either Yes or No.  
All clinically important abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return either to baseline or to a level deemed acceptable by the 
investigator or his/her designated representative, or until a diagnosis that explains them is made.  
The criteria for determining whether an abnormal laboratory test result should be reported as an 
adverse event are as follows: 
1. test result is associated with accompanying symptoms, and/or 
2. test result requires additional diagnostic testing or medical/surgical intervention (merely 
repeating an abnormal test, in the absence of any of the above conditions, does not meet 
criteria for a reportable AE), and/or 
3. test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment or other therapy, and/or 
4. test result leads to any of the outcomes included in the definition of a serious adverse 
event, and/or 
5. test result is considered to be an adverse event by the investigator or sponsor, and/or 
6. test result is CTCAE v4.0 grade 3 or above 
Any abnormal test result that is determined to be an error does not require reporting as an 
adverse event, even if it did meet one of the above conditions except for condition #4.  
Clinically significant laboratory results deemed Related to IP must be recorded in the patient’s 
CRF. 
6.7.4.1 
Serious Adverse Event Reporting Procedures (on-site SAEs) 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 33 of 69 
 
New SAEs and SUSARS will be collected and recorded throughout the study period, 
from the signing of the informed consent through 28 days after the final dose of 
abiraterone acetate.  Ongoing SAE/SUSARs with a causal relationship to the 
investigational product will be followed until the event or its sequelae resolve or stabilize 
at a level acceptable to the investigator or designee.  Contact information, fax numbers 
and email addresses for FDA, CC-IRB and Janssen Services LLC are collated in 
Appendix 4.  
Reporting to the FDA 
The investigator is responsible for reporting SAE/SUSARs to the FDA within 24 
business hours of discovery or notification of the event.  The investigator or designee 
will complete Form FDA-3500A for submission to MedWatch.  Form may be completed 
online via https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm (as of 
Jan2012), or printed and faxed as instructed online.  All deaths within 28 days of final IP 
dose, whether SUSARs or not, will be reported in an expedited manner to the FDA. 
Reporting to IRB 
All serious adverse events that occur after the subject has signed the informed consent 
form or during the study at the University of Washington or Seattle Cancer Care Alliance 
must be reported to the Cancer Consortium IRB (CC-IRB, fax 206-667-6831).  Report 
must be transmitted within 24 business hours of discovery or notification of the event 
and the event must meet institutional reporting guidelines.  The Adverse Event Reporting 
Form 
is 
available 
online, 
http://extranet.fhcrc.org/EN/sections/iro/irb/forms/index.html#Reporting (as of Jan2012).  
SUSARs will be reported on the Expedited Reporting Form for Unanticipated Problems 
or Noncompliance.  Special Reporting Situations (SRS) will be reported to CC-IRB 
either immediately or at annual renewal, upon consultation with IRB staff.  The SAE, 
SUSAR or SRS should be recorded on the appropriate case report form (CRF).   
Reporting to Janssen Services, LLC 
The investigator or designee will transmit SAE/SUSAR on Form FDA-3500A.  The form 
will be transmitted to Janssen Services LLC’s designated fax number (or designated 
email address) within 24 business hours of becoming aware of the event(s).  The form 
will be completed in English, and will include as much information as possible regarding 
the SAE/SUSAR.   
All available clinical information relevant to the evaluation of an SAE, SUSAR, Adverse 
Events of Special Interest, and Special Reporting Situations including pregnancy reports 
(with or without an AE), including paternal exposure, are required. 
 The investigator is responsible for ensuring that these cases from clinical studies are 
complete and if not are promptly followed-up.  This includes ensuring the reports are 
fully investigated and thoroughly documented by the investigator and that follow-up 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 34 of 69 
 
information is summarized (e.g. hospital records, coroner’s reports, autopsy results) 
and recorded on the appropriate forms. 
 A study case is not considered complete until all clinical details needed to interpret 
the case are received and the event has resolved, or otherwise explained, or the patient 
is lost to follow-up. Reporting of follow-up information should follow the same 
timeline as initial reports. 
 Janssen Services, LLC, requests copies of the study site’s correspondence with 
regulatory authorities and ethics committees regarding all serious adverse events, 
regardless of causality.  Janssen prefers to receive these copies by facsimile within 24 
hours of transmission to or from the actual authorities. 
Reports of SAEs should be signed and dated by the principal investigator.  In the absence 
of the PI, reports should be signed and dated by the individual reporting the event.  If s/he 
is not medically licensed, the report should also be signed by a licensed medical 
practitioner, preferably a sub-investigator for this protocol.  The PI will review and sign 
the report at the next opportunity.   
Each report should contain the following information: 
 Protocol number 
 Subject number 
 Disease/histology, if applicable 
 Date the event occurred 
 Description of the SAE 
 Relationship of the event to treatment (abiraterone acetate), or other causality 
 Whether the event was “expected’ 
 Severity of the event 
 Intervention 
 Outcome of the event 
 Detailed text that includes the following information: 
- 
An explanation of how the SAE was handled 
- 
A description of the patient’s condition 
- 
Indication whether the subject remains on study  
- 
Recommendation whether an amendment will need to be made to the protocol 
and/or the consent form.  
Relevant, redacted medical records should be provided as soon as they become available; 
autopsy reports should be provided for deaths if available.  Determination of 
expectedness will be based on the contents of the current Investigator’s Brochure or 
package insert.  
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 35 of 69 
 
If a subject is permanently withdrawn from the study because of a serious adverse event, 
this information must be included in the End of Study Case Report Form as well as all 
SAE/SUSAR reports.  
6.7.4.2 Annual Safety Reports 
In addition to the expedited reporting, sponsor shall submit, once a year throughout the 
clinical trial or on request a safety report to the competent authority and Institutional 
Review Board, taking into account all new available safety information received during 
the reporting period.   
Cumulative logs of off-site SAEs, SUSARS and Special Reporting Situations will be 
forwarded to the IRB of record at least annually.   
6.7.5 Management of Study Drug-Related Events  
Based upon experience from Phase 1 and ongoing Phase 2 studies, abiraterone acetate is 
generally well tolerated.  The most common adverse events related to abiraterone acetate 
monotherapy include fatigue due to reduced cortisol level as a result of CYP17 inhibition; and 
hypertension, fluid retention, and hypokalemia due to mineralocorticoid excess caused by 
compensatory ACTH drive.  In this study, the concomitant administration of prednisone is 
expected to mitigate these side effects by supplementing cortisol and abrogating ACTH drive.   
During study, corticosteroid treatment will be provided.  It has been documented that following 
prolonged therapy with corticosteroids, patients 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 evidence of adrenal insufficiency.   
For guidance on management of side effects of glucocorticoid usage, symptoms related to 
castration (androgen deprivation), severe and refractory headaches, fatigue, or other toxicities 
not listed below please contact the Principal Investigator at each institution.   
Re-initiation of study treatment after resolution of adverse events must be discussed with and 
approved by the Principal Investigator. 
6.7.5.1 Management of 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 (6) and Clinical Pharmacology (12.1)].  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 Abiraterone acetate 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 36 of 69 
 
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. 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 37 of 69 
 
Serum K+ 
Action 
Further Action and/or 
Maintenance 
 
Low K+ 
and/or history of 
Hypokalemia 
 
Weekly (or more frequent) 
laboratory electrolyte evaluations 
Titrate dose to maintain a Serum K+ 
>3.5mM <5.0mM (Maintenance of 
pts. at > 4.0mM is recommended) 
 
< 3.5mM - 3.0mM 
 
Initiate oral K+ supplementation 
Titrate dose to maintain a Serum K+ 
>3.5mM <5.0mM (Maintenance of 
pts at > 4.0mM is recommended) 
 
< 3.0mM 
Withhold Abiraterone acetate 
(study) treatment and initiate IV 
K+ and cardiac monitoring 
 
6.7.5.2 Management of 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.  
6.7.5.3 Management of Hepatotoxicity 
All patients will undergo assessment of liver function prior to enrollment on study.  For 
patients who develop hepatotoxicity during treatment with abiraterone at 1000 mg daily 
(ALT and/or AST greater than 5x ULN or total bilirubin greater than 3x ULN), interrupt 
treatment with abiraterone.  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. The safety of abiraterone 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. Patients who develop hepatotoxicity (ALT and/or AST greater than 5x ULN 
or total bilirubin greater than 3x ULN) during treatment with dose escalated abiraterone 
at 1000 mg twice daily will be removed from study.  
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 38 of 69 
 
6.7.5.4 Management of Hepatic Impairment 
Patients with Child-Pugh Class B or C hepatic impairment will not be treated on study.  
6.8 DOSAGE FORMS AND Criteria for Discontinuation of Study 
The development of > 20% incidence of grade 3 or grade 4 toxicity (CTCAE v4.0) during 
administration of abiraterone acetate in the treatment of patients in cohort 3 will prompt review of 
toxicity and if appropriate, suspension of study.   
6.9 Withdrawal from Study 
The investigator may withdraw a patient from any phase of the study for any of the following 
reasons.  
 Discontinuation of treatment criteria as defined in Section 6.8 
 Dosing noncompliance:  If a patient misses 14 or more doses within a 4 week period the 
patient should be discontinued from the study treatment period.   
 Sustained Side Effects:  Patients who have sustained toxicities, such as hyperglycemia or 
hypertension that do not return to NCI CTCAE (version 3) Grade 1 or less with appropriate 
medical management, should be discontinued from the study treatment.   
 Administration of prohibited medications:  The patient will be discontinued from the protocol 
treatment when prohibited drug is administered. Supportive care medications are permitted 
with their use following institutional guidelines.  The concurrent administration of other 
anticancer therapy, including cytotoxic, hormonal (except 
LHRH agonists), or 
immunotherapy is prohibited during study treatment Phase.  Use of other investigational drug 
therapy for any reason is prohibited. 
 Patient withdraws consent.  In this event, the reason(s) for withdrawal must be documented 
and clarification if withdrawal of consent includes follow-up phase for progression data 
collection.  A patient’s decision to take part in the study is voluntary and he may choose not 
to take part in the study or to stop taking part at any time.  If he chooses not to take part or to 
stop at any time, it will not affect his future medical care or medical benefits. 
If a subject terminates the study early, an Early Termination visit will be performed.  
 
7 
STUDY ACTIVITIES 
7.1 Study Visit Overview 
All protocol required therapy will be provided by prescription and taken by participant on an 
outpatient basis.  A baseline biopsy of metastasis is performed prior to beginning therapy.  Patients 
will be treated with abiraterone acetate 1000mg administered orally once daily in combination with 
prednisone 5 mg administered orally twice daily.  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.  
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 39 of 69 
 
Patients will then continue on combined therapy until progression or taken off study at the PI’s 
discretion.  Patients will be evaluated clinically and with laboratories on a monthly basis throughout 
protocol treatment.  A metastasis biopsy will be done while still on abiraterone acetate at 4 weeks 
(cohort 1), or at 12 weeks (cohort 2) or at the time of progression (cohort 3).  After progression, 
dose escalation to 1000 mg twice daily will be allowed.  The tumor biopsy at designated time point 
(Baseline, 4 weeks, 12 weeks or progression) is mandatory and can be done +/- 30 days of initiation 
of therapy for baseline biopsy and at approximate timepoints for 4 and 12 week timepoints.  
Situations where the patient stops protocol therapy for reasons other than progression should be 
discussed with the PI if it is felt that the biopsy would not represent disease biology at the relevant 
time point.  
Expected toxicities and potential risks as well as dose modifications for abiraterone acetate are 
described in Section 6.7.5.  No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the participant's malignancy. 
Screening Period 
Patients for the study will be recruited from sites from within the Seattle Cancer Care Alliance 
(SCCA). Patients will be identified as eligible for the study and the study will be discussed with the 
patient by their provider.  If patients are interested in participating, they will be counseled and 
informed consent will be obtained by one of the investigators.    
Screening procedures to be completed within 30 days prior to the start of study treatment (Day 1): 
 Informed consent 
 Registration 
 Medical history and demographics  
 Physical examination, including weight and height 
 Vital signs including blood pressure, heart rate, respiratory rate.  
 Assessment of ECOG Performance Status 
 12 lead ECG 
 Adverse event baseline 
 Echocardiogram or MUGA 
 Lab test: 
◦ 
CBC:  WBC with differential count, RBC, hemoglobin, hematocrit, platelets. 
◦ 
Liver function tests (LFT’s – AST, ALT, alkaline phosphatase, total bilirubin),   
◦ 
Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, BUN, 
glucose, calcium, magnesium. 
◦ 
PSA (must be sampled prior to DRE) 
◦ 
Total testosterone optimally drawn before 10 AM  
◦ 
Research hormone levels optimally drawn before 10 AM  
 Bone scan and CT or MRI of the abdomen/pelvis 
 Chest film or chest CT 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 40 of 69 
 
 miRNA collection 
 Concomitant medications listing: 
Obtain a complete and thorough listing of all prescription and nonprescription (over the 
counter) medications currently taken including pain medications.  This also includes any 
nutritional supplements and/or herbal preparations. 
7.2 Pre-Treatment Biopsy 
Patients will undergo pretreatment CT or ultrasound guided needle biopsies of a metastasis felt 
amenable to biopsy by the performing radiologist (6 cores) following registration.  
7.3 Treatment Period 
7.3.1 Visit 1 (Study Day 1) 
 Patients will continue on Lupron throughout study 
 Patients will start Abiraterone acetate 1000 mg PO daily. 
 Patients will start prednisone 5 mg PO twice daily  
The following procedures should be completed at this visit: 
 Evaluation of patient compliance, adverse events and concomitant medications 
 Physical exam 
 Vital signs, including blood pressure, heart rate, respiratory rate, and weight. 
 ECOG performance status 
 CBC:  WBC with differential count, RBC, hemoglobin, hematocrit, platelets. 
 Liver function tests (LFT’s - AST, ALT, alkaline phosphatase, total bilirubin),   
 Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, BUN, 
calcium, , magnesium, glucose) 
 PSA 
 Research hormone levels, optimally drawn before 10 AM. 
7.3.2 Subsequent visits 
During the first three months of therapy (Cycles 1-3) patients will undergo hepatic function 
testing (AST, ALT, alkaline phosphatase, total bilirubin) every 2 weeks (± 1 week).  Patients 
who dose-increase to1,000 mg bid will resume hepatic function testing every two weeks (± 1 
week) until end of treatment and follow-up. 
Every 4 weeks after the initial dose of abiraterone acetate, all subjects will return every 4 weeks 
(± 4 days) where the following procedures will occur: 
 Patients will be evaluated for compliance, adverse events, and concomitant medications 
 Physical exam 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 41 of 69 
 
 Vital signs, including blood pressure, heart rate, respiratory rate and weight.  
 ECOG performance status 
 CBC:  WBC with differential count, RBC, hemoglobin, hematocrit, platelets. 
 Liver function tests (LFT’s - AST, ALT, alkaline phosphatase, total bilirubin) – to be 
performed monthly after the first three months of therapy,   
 Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, BUN, 
calcium, magnesium, glucose) 
 PSA and research hormone levels 
 Bone scan and CT or MRI of the abdomen/pelvis and Chest film or chest CT will be 
repeated every 12 weeks or as clinically indicated.  
Patients will undergo planned repeat tumor biopsy at one of the following time points:  4 weeks 
(cohort 1), 12 weeks (cohort 2) or progression (cohort 3).  Patients who progress prior to 
planned biopsy in cohorts 1 and 2 will undergo progression biopsy and additional patients will 
be enrolled in cohorts 1 or 2. 
 Patients will undergo pretreatment CT or ultrasound guided needle biopsies of a 
metastasis felt amenable to biopsy by the performing radiologist (6 cores) following as 
per the Tissue Acquisition SOP listed in the Laboratory manual. 
 Research hormone levels, optimally drawn before 10 AM 
  miRNA levels drawn 
7.3.3 Pharmacokinetics 
All patients in all cohorts will be offered the option of participating in pharmacokinetic analysis 
at the time of progression while receiving 1000 mg daily and then after dose escalation to 1000 
mg twice daily.  The analysis of pharmacokinetics at progression will explore the potential that 
induction of abiraterone metabolism may result in suboptimal pharmacokinetics and subsequent 
pharmacodynamic effect on tumor as a mechanism of secondary resistance to abiraterone 
therapy.  There is limited data available regarding abiraterone pharmacokinetics after prolonged 
dosing of abiraterone and there is evidence that ability of other, less effective CYP17 inhibitors 
such as ketoconazole, to suppress androgen levels wanes with time due either to incomplete 
CYP17 block or altered pharmacokinetics [31, 32].  The addition of formal pharmacokinetic 
evaluations before and after dose would provide important information about secondary 
resistance to abiraterone therapy.  The proposed pharmacokinetic sampling would be as follows:  
 At progression, dose = 1000 mg daily. Plasma samples will be drawn prior to daily dose 
and then at 1, 2, 3, 4, 6, 8, and 24 hours post dose (Note: patient will take the next daily 
dose AFTER the 24-hour post-dose sample is collected) 
 7-14 days after dose increase to 1000 mg twice daily. Plasma samples will be drawn prior 
to AM dose and  1, 2, 3, 4, 6, 8, and 12 hours post AM dose (Note: patient will take the 
evening dose AFTER the 12-hour post-dose sample is collected) 
Special Instructions: 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 42 of 69 
 
On the day of PK collection, patients MUST take abiraterone acetate (morning dose only) after 
an overnight fasting (~10 hours) and no food should be consumed until 1 hour after dosing. 
Patients who are taking abiraterone acetate 1000 mg twice daily should take the morning dose 
and evening dose approximately 12 hours apart. 
PK sample collection, processing, storage, and shipping instructions are presented in Appendix 
6. 
7.3.4 Dose escalation  
All patients in all cohorts will be offered the option of dose escalation to 1000 mg twice daily.  
This dose escalation will explore whether subsequent response is associated with higher than 
anticipated tissue testosterone levels and/or CYP17 levels will explore the potential that 
resistance may be mediated by upregulation of the abiraterone acetate target CYP17 with 
subsequent tumor androgen maintenance, as seen in preclinical studies cited in section 1.1.  As 
previously noted, in published phase I studies, there was no grade 3 or 4 toxicity in patients 
treated with 2000 mg daily abiraterone acetate achieved proportional increases in serum 
abiraterone acetate levels [26].  Those patients who go on to therapy with abiraterone acetate 
1000 mg twice daily will be monitored for toxicity and progression exactly as those patients 
treated at 1000 mg daily except that liver function tests will be performed every 2 weeks 
indefinitely.  At the time of subsequent progression, abiraterone acetate will be discontinued.  
There is no minimum or maximum number of patients who may dose escalate.  Target 
enrollment for PK sampling is 20 patients.    
The rationale for dose escalation to 1000 mg twice daily compared to 2000 mg once daily is that 
previous data indicated that there was minimal increase in abiraterone PK exposure when the 
dose increased from 1000 mg QD to 2000 mg QD. Given the poor solubility of abiraterone 
acetate, this less than dose proportional increase in PK exposure was most likely caused by 
solubility-limited absorption. Administering the total daily dose (2000 mg per day) in two 
divided doses (1000 mg BID) may help circumvent this issue by increasing the soluble fraction 
of abiraterone acetate thereby enhancing overall absorption.  
If a subject terminates the study early or at progression, a Termination visit with procedures as 
per the Study Calendar, and as follows.  
 Patients will be evaluated for compliance, adverse events, and concomitant medications 
 Physical exam 
 Vital signs, including blood pressure, heart rate, respiratory rate and weight.  
 ECOG performance status 
 CBC:  WBC with differential count, RBC, hemoglobin, hematocrit, platelets. 
 Liver function tests (LFT’s - AST, ALT, alkaline phosphatase, total bilirubin),   
 Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, BUN, 
calcium, phosphorus, magnesium, glucose) 
 PSA, miRNA and research hormone levels will be drawn 
 Abiraterone acetate will be discontinued 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 43 of 69 
 
8 
PLANNED STATISTICAL METHODS 
8.1 General Considerations 
The primary endpoint is evaluation of the decrease of tissue testosterone from baseline (the last 
value on or before the date of first study treatment) to the 4-week time point. Sample size 
calculations for this endpoint are based on xenograft studies of abiraterone acetate. Planned analysis 
of primary and exploratory endpoints involves numerical and graphical summaries and standard 
statistical hypothesis tests and linear-model-based inference. 
8.2 Determination of Sample Size 
Basal tissue testosterone and testosterone after abiraterone acetate treatment at response were 
derived from xenograft studies of abiraterone acetate effect in castrate male mice. Baseline tissue 
testosterone in untreated CRPC xenografts was 0.687 ± 0.364 (mean ± SD) pg/mg, approximating 
that seen in human CRPC metastases. Nadir tissue testosterone after 7–21 days was 0.027 ± 0.009 
pg/mg, approximating 4-week levels. Using the SD of testosterone derived from untreated 
observations (0.364 pg/mg), 6 patients provide 94% power to detect the anticipated 0.660 pg/mg 
difference in tissue testosterone relative to baseline based on a 2-sided paired t-test with alpha 5%. 
However, in our experience only 75% of CT and ultrasound guided biopsies yield evaluable tissue; 
consequently 6/10 patients are expected to provide evaluable tissue measurements at both baseline 
and after 4 weeks. 
Data Analysis: Tissue testosterone measurements will be summarized numerically and graphically 
using plots of patient- and cohort-specific longitudinal patterns and side-by-side boxplots at each 
time point. Other tissue androgen levels will be similarly graphed and examined. 
As in the power calculation, we will test the primary endpoint—change in tissue testosterone after 4 
weeks—using a 2-sided paired t-test and consider an attained significance level of 5% statistically 
significant. We will also test exploratory hypotheses—change in tissue testosterone after 12 weeks 
and at progression—using the same test and significance level. We anticipate power to detect 
change in tissue testosterone after 12 weeks to be similar to that after 4 weeks. Based on 
preliminary data from xenograft studies, post-nadir tissue testosterone rose to 0.222 ± 0.246 pg/mg 
at progression; we therefore anticipate that, using the SD of testosterone derived from untreated 
observations (0.364 pg/mg), 7 patients achieving progression will provide 80% power to detect the 
anticipated 0.465 pg/mg difference in tissue testosterone relative to baseline based on a 2-sided 
paired t-test with alpha 5%. 
Analysis of microarray data will evaluate change in gene expression (expressed as log ratio relative 
to human gold standard) by fitting linear models for each gene to test for changes in each cohort 
relative to baseline while controlling for false discovery using limma, qvalue, and related 
Bioconductor statistical analysis software packages. 
8.3 Analysis Populations  
All patients who receive at least one dose of study drug will be included in the analysis of safety 
(Safety Population). 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 44 of 69 
 
8.4 Demographics and Baseline Characteristics 
Demographic variables will include age, race, ethnicity, height, and weight. Baseline disease 
characteristics will include PSA, Gleason Grade, and clinical stage.  
8.5 Safety Evaluations 
Treatment emergent adverse events (AEs) directly related to abiraterone acetate 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, version 4.0 (NCI-
CTCAE). An acute adverse event will be defined as an adverse event occurring up to and including 
90 days after initiation of RT.  A late adverse event will be defined as an adverse event occurring 
more than 90 days after the initiation of RT.  Unacceptable toxicity is defined as grade 3 or higher 
toxicity.  Incidence of AEs will be summarized by system organ class (SOC) and preferred term 
(PT).  Adverse events will be summarized by grade, according to the worst grade experienced.  In 
the summary of AE, an AE occurs more than once within a SOC and PT will be counted only once 
using the worst grade experienced.   
All adverse events resulting in discontinuation, dose modification, dosing interruption, and/or 
treatment delay of study drug will also be listed and tabulated by preferred term. 
Clinical laboratory test results will be collected pretreatment and through 28 days post last dose of 
study treatment.  All laboratory test results will be classified according to the NCI CTCAE criteria.  
Standard reference ranges will be used for missing or discrepant normal ranges.  Baseline 
laboratory test values are the results from the last blood samples drawn on or prior to the first day of 
study treatment.  On-study laboratory test values are those results from blood samples drawn a day 
after the first study treatment up until 30 days after the last dose of abiraterone acetate. 
Mean change from baseline in laboratory test values at each visit will be provided.  On-study 
clinical laboratory test abnormalities will be summarized.  Shifts in laboratory test values will also 
be summarized. 
Electrocardiograms data will be descriptively summarized for QTc, PR interval, and QRS at each 
assessment. Comparison between baseline and maximum on-study QTc will also be presented.  
Both Fredericia and Bazett corrections will be reported. 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 45 of 69 
 
9 
REFERENCE LIST 
1. 
Huggins C, Hodges CV: Studies on prostatic cancer. I. The effect of castration, estrogen and 
androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer 
Res 1941, 1:293-297. 
2. 
Forti G, Salerno R, Moneti G, Zoppi S, Fiorelli G, Marinoni T, Natali A, Costantini A, Serio M, 
Martini L et al: Three-month treatment with a long-acting gonadotropin-releasing hormone 
agonist of patients with benign prostatic hyperplasia: effects on tissue androgen 
concentration, 5 alpha-reductase activity and androgen receptor content. J Clin Endocrinol 
Metab 1989, 68(2):461-468. 
3. 
Geller J, de la Vega DJ, Albert JD, Nachtsheim DA: Tissue dihydrotestosterone levels and 
clinical response to hormonal therapy in patients with advanced prostate cancer. J Clin 
Endocrinol Metab 1984, 58(1):36-40. 
4. 
Mohler J, Gregory C, Ford III O, Kim D, Weaver C, Petrusz P, Wilson E, French F: The 
Androgen Axis in Recurrent Prostate Cancer. Clinical Cancer Res 2004, 10(2):440-448. 
5. 
Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD, 
Nelson PS: Maintenance of intratumoral androgens in metastatic prostate cancer: a 
mechanism for castration-resistant tumor growth. Cancer Res 2008, 68(11):4447-4454. 
6. 
Geller J, Liu J, Albert J, Fay W, Berry CC, Weis P: Relationship between human prostatic 
epithelial cell protein synthesis and tissue dihydrotestosterone level. Clin Endocrinol (Oxf) 
1987, 26(2):155-161. 
7. 
Geller J, Albert J: Effects of castration compared with total androgen blockade on tissue 
dihydrotestosterone (DHT) concentration in benign prostatic hyperplasia (BPH). Urol Res 
1987, 15(3):151-153. 
8. 
Dehm SM, Tindall DJ: Regulation of androgen receptor signaling in prostate cancer. Expert 
Rev Anticancer Ther 2005, 5(1):63-74. 
9. 
Kojima S, Suzuki H, Akakura K, Shimbo M, Ichikawa T, Ito H: Alternative antiandrogens to 
treat prostate cancer relapse after initial hormone therapy. J Urol 2004, 171(2 Pt 1):679-
683. 
10. 
Scher HI, Buchanan G, Gerald W, Butler LM, Tilley WD: Targeting the androgen receptor: 
improving outcomes for castration-resistant prostate cancer. Endocr Relat Cancer 2004, 
11(3):459-476. 
11. 
Small EJ, Vogelzang NJ: Second-line hormonal therapy for advanced prostate cancer: a 
shifting paradigm. J Clin Oncol 1997, 15(1):382-388. 
12. 
Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser TC, Willi N, Mihatsch MJ, 
Sauter G, Kallioniemi OP: Survey of gene amplifications during prostate cancer progression 
by high-throughout fluorescence in situ hybridization on tissue microarrays [published 
erratum appears in Cancer Res 1999 Mar 15;59(6):1388]. Cancer Res 1999, 59(4):803-806. 
13. 
Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL: 
Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004, 10(1):33-39. 
14. 
Gregory C, Hamil K, Kim D, Hall S, Pretlow T, Mohler J, French F: Androgen receptor 
expression in androgen-independent prostate cancer is associated with increased 
expression of androgen-regulated genes. Cancer Research 1998, 58:5718-5724. 
15. 
Mizokami A, Koh E, Fujita H, Maeda Y, Egawa M, Koshida K, Honma S, Keller ET, Namiki M: 
The adrenal androgen androstenediol is present in prostate cancer tissue after androgen 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 46 of 69 
 
deprivation therapy and activates mutated androgen receptor. Cancer Res 2004, 64(2):765-
771. 
16. 
Holzbeierlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, Ryan C, Smith S, Scher H, 
Scardino P et al: Gene expression analysis of human prostate carcinoma during hormonal 
therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J 
Pathol 2004, 164(1):217-227. 
17. 
Luo J, Dunn TA, Ewing CM, Walsh PC, Isaacs WB: Decreased gene expression of steroid 5 
alpha-reductase 2 in human prostate cancer: implications for finasteride therapy of 
prostate carcinoma. Prostate 2003, 57(2):134-139. 
18. 
Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk SP: 
Increased expression of genes converting adrenal androgens to testosterone in androgen-
independent prostate cancer. Cancer Res 2006, 66(5):2815-2825. 
19. 
Attard G, Reid AH, Olmos D, de Bono JS: Antitumor activity with CYP17 blockade indicates 
that castration-resistant prostate cancer frequently remains hormone driven. Cancer Res 
2009, 69(12):4937-4940. 
20. 
Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk SP, Matsumoto AM, Nelson PS, 
Montgomery RB: Resistance to CYP17A1 inhibition with abiraterone in castration resistant 
prostate cancer: Induction of steroidogenesis and androgen receptor splice variants Clinical 
Cancer Research 2011, In press. 
21. 
Attard G, Reid AH, A'Hern R, Parker C, Oommen NB, Folkerd E, Messiou C, Molife LR, Maier 
G, Thompson E et al: Selective inhibition of CYP17 with abiraterone acetate is highly active 
in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009, 27(23):3742-
3748. 
22. 
Reid AH, Attard G, Danila DC, Oommen NB, Olmos D, Fong PC, Molife LR, Hunt J, Messiou 
C, Parker C et al: Significant and sustained antitumor activity in post-docetaxel, castration-
resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 2010, 
28(9):1489-1495. 
23. 
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman 
OB, Jr., Saad F et al: Abiraterone and increased survival in metastatic prostate cancer. N 
Engl J Med 2011, 364(21):1995-2005. 
24. 
Mohler JL, Gregory CW, Ford OH, 3rd, Kim D, Weaver CM, Petrusz P, Wilson EM, French FS: 
The androgen axis in recurrent prostate cancer. Clin Cancer Res 2004, 10(2):440-448. 
25. 
de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen 
LW, Pienta KJ, Raghavan D: Circulating tumor cells predict survival benefit from treatment 
in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008, 14(19):6302-6309. 
26. 
Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins 
V, Folkerd E et al: Phase I clinical trial of a selective inhibitor of CYP17, abiraterone 
acetate, confirms that castration-resistant prostate cancer commonly remains hormone 
driven. J Clin Oncol 2008, 26(28):4563-4571. 
27. 
Ryan CJ, Smith MR, Fong L, Rosenberg JE, Kantoff P, Raynaud F, Martins V, Lee G, Kheoh T, 
Kim J et al: Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating 
clinical activity in patients with castration-resistant prostate cancer who received prior 
ketoconazole therapy. J Clin Oncol 2010, 28(9):1481-1488. 
28. 
Kalhorn TF, Page ST, Howald WN, Mostaghel EA, Nelson PS: Analysis of testosterone and 
dihydrotestosterone from biological fluids as the oxime derivatives using high-performance 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 47 of 69 
 
liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2007, 
21(19):3200-3206. 
29. 
Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, 
Nguyen HM, Sun H et al: Castration resistance in human prostate cancer is conferred by a 
frequently occurring androgen receptor splice variant. J Clin Invest 2010, 120(8):2715-2730. 
30. 
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, 
Higano C, Bubley GJ, Dreicer R et al: Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of 
the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008, 26(7):1148-1159. 
31. 
Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, 
Vogelzang NJ.  Antiandrogen withdrawal alone or in combination with ketoconazole in 
androgen-independent prostate cancer patients: a phase III trial (CALGB 9583).  J Clin 
Oncol. 2004 22(6):1025-33. 
32.  
Ryan CJ, Halabi S, Ou SS, Vogelzang NJ, Kantoff P, Small EJ. Adrenal androgen levels as 
predictors of outcome in prostate cancer patients treated with ketoconazole plus 
antiandrogen withdrawal: results from a cancer and leukemia group B study.  Clin Cancer 
Res. 2007 13(7):2030-7. 
 
 
 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

Clinical Study Protocol:PD Abiraterone acetate 
____________________________________________________________________ 
Confidential 
Page 48 of 69 
 
10 APPENDICES 
APPENDIX 1 - SCHEDULE OF EVENTS 
 
 
 
 
Screening   
Day -30 
to -1 
Day 1 of 
Every 
Cycle1 
Every 14 
days Cycles 
1-3 (± 1 
wk)2, 3 
Tumor 
biopsy at 4 
wks 
Cohort 1 
Every 12 
wks (+/- 
1 wk) 
Tumor 
biopsy at 
12 wks 
Cohort 2 
Tumor biopsy at 
progression 
Cohort 3 
Termination 
visit 
Informed Consent  
X 
 
 
 
 
 
 
 
Registration/Randomization 
X 
 
 
 
 
 
 
 
Medical History  
X 
X 
 
 
 
 
 
 
Physical exam 
X 
X 
 
 
 
 
 
X 
Vital Signs  
X 
X 
 
 
 
 
 
X 
ECOG performance status 
X 
X 
 
 
 
 
 
X 
12 Lead ECG 
X 
 
 
 
 
 
 
 
MUGA/Echo 
X 
 
 
 
 
 
 
 
CBC (w/ platelets & differentials) 
X 
X 
 
 
 
 
 
X 
Serum chemistry & electrolytes 
X 
X 
 
 
 
 
 
X 
Hepatic function 
X 
X 
X 
 
 
 
 
X 
PSA 
X 
X 
 
 
 
 
 
X 
Total testosterone  
X 
 
 
 
 
 
 
 
Research serum hormones  
X 
X 
 
X 
 
X 
X 
X 
Bone scan, and CT or MRI of pelvis/abdomen 
X 
 
 
 
X 
 
 
 
Chest film or chest CT 
X 
 
 
 
X 
 
 
 
Dosing Compliance Check 
 
X 
 
 
 
 
 
X 
Concomitant medications 
X 
X 
 
 
 
 
 
X 
Adverse Events 
X 
X 
 
 
 
 
 
X 
Tumor Biopsies 
X 
 
 
X 
 
X 
X 
 
miRNA collection 
X 
 
 
X 
 
X 
X 
X 
Pharmacokinetics 
 
 
 
 
 
 
X2 
 
Dose escalation  
 
 
 
 
 
 
X3 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 49 of 69 
1 Screening procedures need not be repeated if performed within 7 days of Day 1. 
2 Pharmacokinetic analysis will be performed at progression at 1000 mg daily and 7-14 days after dose escalation to 1000 mg twice daily. PK 
analysis is elective 
3 Hepatic function monitoring every two weeks will resume after dose escalation. 
 Baseline evaluations will be done within 30 days prior to start of therapy. All screening should be complete prior to registration. All study 
assessments and medications should be administered within 5 days of the protocol-specified date, unless otherwise noted.  
 If chest imaging does not demonstrate metastatic prostate cancer, repeat imaging is not necessary.  
 Tumor biopsy can be scheduled within 30 days before starting study medication. Patients will be registered before having biopsy. Preferred 
days of the week are Monday-Thursday to optimize processing.  
 The tumor biopsies within each cohort are mandatory    
 Physical Exam will include blood pressure, respiration, heart rate, and weight.  Height will be measured at screening visit only. 
 Androgen measurements should be drawn before 10:00AM if possible. 
 Hepatic function includes AST, ALT, alkaline phosphatase and total bilirubin. 
 Patients dose escalated to 1000 mg twice daily will continue to be followed as they were prior to progression except that hepatic function will 
be tested every 2 weeks until there is evidence of additional progression.    
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 50 of 69 
APPENDIX 2 - TISSUE ACQUISITION SOP 
 
Laboratory manual 
Tissue acquisition  
Separate addendum  
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 51 of 69 
APPENDIX 3 - TREATMENT SCHEMATIC 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 52 of 69 
APPENDIX 4 - ADVERSE EVENTS 
 
JANSSEN SERVICES, LLC Adverse Event Reporting Requirements for “Interventional 
Studies” 
 
I. Overview 
As the sponsor of the Study, the University of Washington Medical Center (UWMC) 
and/or Bruce Montgomery, MD shall be solely responsible for complying, within the 
required timelines, with any safety reporting obligation towards the competent Health 
Authorities, the IRB/ECs and the participating (co- or sub-) investigators, as defined in 
the applicable laws and regulations.  UWMC/Bruce Montgomery MD will be referred to 
as “the investigator” in the text below. 
 
The investigator will submit safety information to the Janssen Services, LLC 
representative identified in the Research Funding Agreement section entitled “Regulatory 
Responsibilities of UWMC/Bruce Montgomery, MD and Adverse Event Reporting.” 
 
The investigator will provide safety reports to the Janssen Services, LLC representative 
on adverse events, pregnancies and product quality complaints as described below. 
 
II. Definitions 
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. 
 
Adverse Events of Special Interest  
Events that the Janssen Services, LLC representative is actively monitoring as a 
result of a previously identified signal (even if non-serious), and are described in 
Section 6.7, above. 
 
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. 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 53 of 69 
J&J Medicinal Product 
The specific J&J drug under study, abiraterone acetate (ZYTIGA™), and any 
other J&J medicinal product.   
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. 
 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered ‘‘serious’’ if, in the 
view of the investigator, it results in any of the following outcomes:  
 Death,  
 a life-threatening adverse event,  
o Life-threatening adverse event or life-threatening suspected 
adverse reaction.  
 An adverse event or suspected adverse reaction is 
considered ‘‘life-threatening’’ if, in the view of the 
investigator, 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, or  
 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. 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 54 of 69 
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 (for this study, 
abiraterone acetate, specified below) 
 pregnancy exposure (maternal and paternal) 
 exposure to a medicinal product from breastfeeding  
 suspected abuse/misuse of a Johnson & Johnson medicinal product, 
inadvertent or accidental exposure to a Johnson & Johnson medicinal 
product any failure of expected pharmacological action (i.e., lack of 
effect) of a Johnson & Johnson medicinal product unexpected therapeutic 
or clinical benefit from use of a Johnson & Johnson medicinal product 
medication error involving a Johnson & Johnson medicinal product with 
or without patient exposure to a Johnson & Johnson medicinal product 
e.g., name confusion) 
 suspected transmission of any infectious agent via a Johnson & Johnson 
medicinal product  
 
III. Management of Adverse Events, Serious Adverse Events and Special Reporting 
Situations 
In general, the investigator must immediately report to the Janssen Services, LLC 
any serious adverse event and Special Reporting Situations, whether or not 
considered drug related.  Study endpoints that are serious adverse events (e.g., all-
cause mortality) must be reported in accordance with the protocol unless there is 
evidence suggesting a causal relationship between the drug and the event (e.g., 
death as a result of anaphylactic reaction or fatal hepatic necrosis).  In that case, 
the investigator must immediately report the event to the Janssen Services, LLC.  
The investigator must record non-serious adverse events and report them to the 
Janssen Services, LLC according to the timetable for reporting as specified either 
in the protocol or to fulfill regulatory reporting requirements. 
 
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: 
 
A Serious Adverse event or Special Reporting Situation must be reported if it 
occurs during a subject’s participation in the Study (whether receiving abiraterone 
acetate or not), from the consent signature date through 28 days of receiving the 
last dose of Study Product. 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 55 of 69 
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. 
 
IV. Recording of Adverse Events, Serious Adverse Events and Special Reporting 
Situations 
Recording should be done in a concise manner using standard, acceptable medical 
terms. 
 
The adverse event recorded should not be a procedure or a clinical measurement 
(i.e., a laboratory value or vital sign) but should reflect the reason for the 
procedure or the diagnosis based on the abnormal measurement. 
 
Preexisting conditions that worsen in severity or frequency during the Study 
should also be recorded (a preexisting condition that does not worsen is not an 
adverse event). 
 
Further, a procedure or surgery is not an adverse event; rather, the event leading 
to the procedure or surgery is considered an adverse event.  Any event requiring 
in-patient hospitalization that occurs during the course of a subject’s participation 
in a trial must be reported as an SAE.  Hospitalizations that do not meet the 
criteria for SAE reporting are: 
A: Reasons described in the Protocol, e.g. drug administration, Protocol-
required testing 
B. Surgery or procedure planned prior to entry into the Study. 
 
If, in the investigator’s judgment, a clinically significant worsening from baseline 
is observed in any laboratory or other test parameter (e.g., electrocardiogram 
(ECG), angiogram), physical exam finding, or vital sign, a corresponding clinical 
adverse event should be recorded. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should 
be recorded as the adverse event, whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided.  For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an adverse event, using appropriate 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 56 of 69 
medical terminology (e.g., thrombocytopenia, peripheral edema, QT 
prolongation). 
 
V. Maintenance of Safety Information 
Safety information will be maintained in a clinical database/repository in a 
retrievable format.  At a minimum, at the end of the treatment phase (= “last 
patient off treatment”) as well as the end of the follow-up phase (= “last patient 
out”) of the Study, the investigator shall provide all adverse events, both serious 
and non-serious, in report format.  However, in certain circumstances more 
frequent review of the safety data may be necessary, e.g., to fulfill a regulatory 
request.  As such, the data shall be made available within a reasonable timeframe 
at Janssen Services, LLC’s request. 
 
VI. Reporting Timelines 
All safety information covered in Exhibit B (SAEs, Adverse Events of Special 
Interest, Special Reporting Situations, and PQCs) should be reported within 24 
business hours of becoming aware of the event(s).  
 
All non-serious AEs should be reported according to the timeframe outlined in the 
Research Funding Agreement section entitled Reporting of Data. 
 
VII. 
Transmission Methods: 
The following methods are acceptable for transmission of safety information to 
the Janssen Services, LLC: 
 Facsimile (fax), receipt of which is evidences in a successful fax transmission 
report, 
 Electronically subject to strict compliance with the following condition: 
Reporting may be done electronically only upon written approval by Janssen 
Services, LLC, which approval must acknowledge that the electronic 
transmission is in an acceptable encrypted email format.  Without such 
acknowledgement, the approval to use an electronic transmission shall not be 
valid.  The Parties hereby acknowledge the importance of strict precautions 
with the use of electronic transmission for the security, protection and 
maintenance of confidentiality of patient health information contained in the 
reports, or 
 Telephone (for business continuity purposes, if fax or authorized electronic 
system is nonfunctional). 
 
Please use the contact information and process information provided by Janssen 
Services, LLC  
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 57 of 69 
VIII. Procedures for Reporting Adverse Events (AE), Serious Adverse Events 
(SAE), Special Reporting Situation, and Product Quality Complaints (PQCs) to 
Janssen Services, LLC 
 
A: Serious Adverse Events (SAE), Adverse Events of Special Interest, and 
Special Reporting Situations 
In clinical trials (including reports unblinded as to treatment for blinded studies) 
involving the Study Product regardless of whether causality with the 
administration of the Study Product is suspected by the investigator.  
 
The investigator will transmit these reports in a form to be provided (or a form 
substantially similar to the form provided and approved for use by Janssen 
Services, LLC in writing) in accordance with Section VII Transmission methods, 
in English within 24 business hours of becoming aware of the event(s) along 
with the investigator’s determination of whether the event was caused by a J&J 
product. 
 
All available clinical information relevant to the evaluation of an SAE, Adverse 
Events of Special Interest, and Special Reporting Situations including pregnancy 
reports (with or without an AE) including paternal exposure are required. 
 
 The investigator is responsible for ensuring that these cases from 
clinical studies are complete and if not are promptly followed-up. This 
includes ensuring the reports are fully investigated and thoroughly 
documented by the investigator and that follow-up information is 
summarized, e.g., hospital records, coroner’s reports, autopsy results 
and recorded on the appropriate forms. 
 A study case is not considered complete until all clinical details 
needed to interpret the case are received and the event has resolved, or 
otherwise explained, or the patient is lost to follow-up.  Reporting of 
follow-up information should follow the same timeline as initial 
reports. 
 Copies of any and all relevant correspondences with regulatory 
authorities and ethics committees regarding any and all serious adverse 
events, irrespective of association with the Study Drug in the course of 
the Study, by facsimile within 24 hours of such report or 
correspondence being sent to applicable health authorities. 
 
B. Product Quality Complaints 
Any PQC, with or without an AE, (including reports of suspicion of 
counterfeiting, diversion, or tampering, and suspected transmission of pathogens) 
will be transmitted by the investigator in the form provided by Janssen Services, 
LLC in accordance with Section VII Transmission methods, in English, within 24 
business hours of becoming aware of the event(s). 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 58 of 69 
 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 59 of 69 
C. Reconciliation of SAEs 
At a minimum, on a quarterly basis and at the end of the Study, Janssen Services, 
LLC will provide to the investigator a listing of all SAEs reported to the Janssen 
Services, LLC.  The investigator will review this listing and provide any 
discrepancies to Janssen Services, LLC. 
 
Upon request, the investigator shall provide Janssen Services, LLC with a 
summary list of all SAEs, and AEs of Special Interest and Special Reporting 
Situation reports to date, within a reasonable timeline, for reconciliation purposes. 
 
IX. Dissemination of Safety Information from Janssen Services, LLC to the 
Investigator(s) 
 
Janssen Services, LLC will provide to the investigator IND safety reports for the 
Study Product as they become available until all subjects in the Protocol have 
completed their last Study visit according to the Protocol (i.e. Last Subject Last 
Visit has occurred).  
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 60 of 69 
APPENDIX 5 – PROGRESSION AND RESPONSE CRITERIA 
Antitumor Effect– Solid Tumors 
Response and progression will be evaluated in this study using the new 
international criteria proposed by the Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) Committee.  
Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study 
treatment will be evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response. Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response. These 
participants will have their response classified according to the definitions stated 
below. (Note: Participants who exhibit objective disease progression or die prior 
to the end of cycle 1 will also be considered evaluable. 
Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one (1) 
lesion that can be accurately measured in at least one dimension with 
longest diameter >20 millimeters (mm) using conventional techniques (CT, 
MRI, x-ray) or >10 mm with spiral CT scan.  Measurable lesions must be at 
least 2 times the slice thickness in mm. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters).  
Reminder: A lesion in a previously irradiated area is not eligible for 
measurable disease unless there is objective evidence of progression of the 
lesion prior to study enrollment. Lesions in previously irradiated areas must 
be clearly identified as such. 
Non-measurable disease. All other lesions (or sites of disease), including 
small lesions (longest diameter <20 mm with conventional techniques or 
<10 mm using spiral CT scan), are considered non-measurable disease. 
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal 
masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable. 
Target lesions. All measurable lesions up to a maximum of 5 lesions per 
organ and 10 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 61 of 69 
imaging techniques or clinically). A sum of the longest diameter (LD) for all 
target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum LD will be used as the reference by which to characterize the 
objective tumor response. 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 10 target lesions should be identified 
as non-target lesions and should also be recorded at baseline. Measurements 
of these lesions are not required, but the presence or absence of each should 
be noted at each follow-up. 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a 
ruler, calipers, or digital measurement tool. All baseline evaluations should 
be performed as closely as possible to the beginning of treatment and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used to assess the anti-tumor 
effect of a treatment. 
Clinical lesions. Clinical lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes). For the 
case of skin lesions, documentation by color photography, including a ruler 
to estimate the size of the lesion, is recommended. 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung; however, CT 
is preferable. 
Conventional CT and MRI. These techniques should be performed with cuts 
of 10 mm or less in slice thickness contiguously. Spiral CT should be 
performed using a 5 mm contiguous reconstruction algorithm. This applies 
to tumors of the chest, abdomen, and pelvis. Head and neck tumors and 
those of extremities usually require specific protocols. 
Tumor Markers.  
Tumor markers alone cannot be used to assess response. Study Outcome 
Measures based on PSA Decline – The following parameters will be 
recorded on a monthly basis.  
 PSA decline will be measured according to PSAWG-2 (2008) criteria. 
 PSA changes will be recorded on all patients. 
 Time to PSA progression (TTP) will be based on revised PSA 
Working Group-2 criteria [30].  
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 62 of 69 
Individual response measures.  
 The maximal decline in PSA for each patient will be recorded for each 
patient. 
 The date of the maximal PSA decline (nadir date) will be recorded for 
each patient, as will the duration from the start of therapy to the nadir 
PSA.  
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline sum 
LD. 
Progressive Disease (PD):  At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions  (new lesions 
must be > slice thickness). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must be 
given. 
Note: If tumor response data is missing, an overall assessment cannot be 
done. However, if there is missing or unevaluable data for non-target 
lesions, but data is available for all target lesions, the overall response for 
that time point will be assigned based on the sum LD of all target lesions. 
Additionally, the assessment of CR cannot be made if there is missing or 
unevaluable data for non-target lesions. In this case, the overall assessment 
would be PR. 
  Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a subject to be considered in complete clinical response 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-
target lesions and/or maintenance of tumor marker level above the normal 
limits. 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 63 of 69 
Progressive Disease (PD): Appearance of one or more new lesions (new 
lesions must be > slice thickness) and/or unequivocal progression of 
existing non-target lesions. 
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must be 
given. 
Note: Although a clear progression of "non-target" lesions only is 
exceptional, in such circumstances, the opinion of the treating physician 
should prevail and the progression status should be confirmed at a later time 
by review of the Principal Investigator (or Protocol Chair). Additionally, the 
cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment is mandatory to differentiate between stable or 
progressive disease status. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The participant's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
NonCR/Non-
PD 
No 
PR 
>4 wks confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented at least once 
>4 wks from baseline 
PD 
Any 
Yes or No PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:    Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as "symptomatic deterioration".  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 64 of 69 
Duration of Response 
Duration of overall response: The duration of overall response is measured 
from the time measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrence or PD is objectively documented, 
taking as reference for PD the smallest measurements recorded since the 
treatment started. 
Duration of overall complete response: The duration of overall CR is 
measured from the time measurement criteria are first met for CR until the 
first date that recurrent disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started. 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the 
duration of time from start of treatment to time of objective disease 
progression.  
Response Review 
Central review of the radiology assessments will be performed via SCCA. 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 65 of 69 
APPENDIX 6 - METHOD FOR PHARMACOKINETIC SAMPLE 
COLLECTION AND HANDLING  
 
PK plasma samples for determination of Abiraterone: 
 
 
1. Materials and Labeling 
 
 
Blood must be collected in Na2EDTA/NaF containing blood collection tubes. Resulting plasma 
samples must be stored in polypropylene storage tubes with polypropylene or polyethylene caps 
(see Ref.). 
 
No tubes with separation gel should be used 
 
All tubes and containers will be labeled with preprinted labels. The preprinted information will 
include the study number, CRF number, treatment or treatment period, scheduled sampling day 
and time as stipulated in the flow chart, and the analyte name (abiraterone). No other information 
will be written on the labels. 
Labels should be applied to the sample tubes as follows: 
 
Apply labels to the sample tubes so that they do not overlap and obscure any information. If 
possible expose an area between the 2 ends of the label to allow viewing of the contents of 
the tube. 
 
Do not alter the orientation of the label on the sample tube. 
 
Apply labels to all tubes in the same manner.  
 
2. Preparation of Plasma Pharmacokinetic Samples 
 
At a timepoint where Abiraterone needs to be determined: 
 
 
Collect 2 mL of blood into the appropriate collection tube (e.g. Vacutainer) at each time point. 
It is important to collect full volume. Immediately invert collection tube end-over-end 5 to 10 
times for mixing of the anticoagulant with the blood collected.  
 
Following blood collection immediately place the Vacutainer tube in an ice bath until 
centrifugation for collection of plasma. 
 
Record the exact date and time of sampling in the CRF, as appropriate. 
 
Centrifuge blood samples within 60 minutes of collection in a clinical centrifuge at 1300 g 
(about 2500-3000rpm) for 10 minutes at 4°C to yield approximately 0.7-1.0 mL of plasma 
from each 2 mL whole blood sample. 
 
Transfer all separated plasma immediately with a clean, disposable glass or polyethylene 
pipette (use a new pipette for each sample) to a pre-labeled polypropylene storage tube (See 
ref.).  
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 66 of 69 
 
Store plasma samples in an upright position, at -20oC or lower until transfer to bioanalytical 
facility. 
 
The time between blood collection and freezing the plasma will not exceed 2 hours. 
 
Ship specimens according to the instructions provided. 
 
Questions regarding handling the plasma pharmacokinetic specimens should be addressed 
to the contact person for the sponsor. 
 
References: 
Blood collection tubes: 
Blood tubes 2 ml plastic Na2EDTA/NaF (Becton Dickinson BD 367587 (US) or BD368520 (EU)) 
 
 
Plasma tubes: 
Clear PP plasma tube: 1.8-ml NUNC Cryotube (Nunc CryoTubes™, Internal thread, 
Polypropylene (PP) tube and screw stopper; cat no: 368632) 
 
 
Shipment of Samples for Drug Measurement 
All samples for Drug Measurement will be sent to the bioanalytical facility in a single 
shipment at the end of the study or in multiple shipments as agreed upon with the 
bioanalytical scientist.  An inventory list must be included with each shipment. The 
sponsor-provided logs can be used as an inventory list. The inventory list must note each 
specimen drawn for each subject, and note any missing specimens. 
 
The investigator must follow the instructions below: 
 For all international shipments, World Courier will be used. For domestic 
shipments, a reliable domestic courier, such as Federal Express will be used. 
 The sponsor contact will be notified by fax or email that a shipment of samples is 
imminent. This notification will be made before the shipping date. As soon as 
shipment day and air bill number(s) are available, the site will e-mail Alex 
Attema, PhD (see next page). The e-mail must specify the study number, the 
number of samples, the time of shipment pick-up and the AWB/tracking number 
and include an electronic sample inventory. 
 Notify the bioanalytical scientist and the courier, at least 24 hours in advance of 
the planned shipment. Provide the courier with the appropriate account number to 
be used, if applicable. 
 Unless agreements were made with the Bioanalysis Scientist, samples will be 
shipped via overnight delivery only on Monday through Wednesday, excluding 
holidays. 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 67 of 69 
 Preferably the frozen samples will be shipped in boxes, sorted by subject and 
sampling time. Boxes will be packed in bags that can withstand dry ice conditions 
(e.g., cryogenic bags). 
 Pack the frozen samples in sufficient quantity of dry ice in appropriate containers, 
to maintain a frozen state for at least 3 days. 
 For all biological samples, follow the International Air Transport Association 
(IATA) regulations for shipment. 
 Ensure that the total package weight does not exceed 27.2 kg (60 pounds). 
 Label the package with the sponsor name and study number. 
 Include a return address (which includes the investigator’s name) on the outside 
of each shipping container. 
 Comply with all courier regulations for the shipment of biological specimens 
(include all paperwork). 
 Retain all documents indicating date, time, and signature(s) of person(s) making 
the shipment, in the study files. 
 Deviations from the above procedure will not result in a protocol amendment if 
approved by the Bioanalysis Scientist. 
 
 
Samples must be sent to: 
PRA International 
To the attention of: 
 
Mr. Alex Attema, PhD. 
PRA International – Early Development Services 
Westerbrink 3 
9405 BJ Assen 
The Netherlands 
 
 
E-mail: Attemaalex@PRAIntl.com  
 
Please be advised, as soon as shipment day and air bill number(s) are available, to notify 
the shipment of the samples to PRA International (e-mail: Attemaalex@PRAIntl.com) 
and to J&J PRD, Hans Stieltjes (e-mail: hstieltj@its.jnj.com ) preferably by e-mail before 
the shipment. 
 
 
 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 68 of 69 
APPENDIX 7 – SUMMARY OF CHANGES 
First Release:  v1.4, dated 9/20/12 
Amendment 1:  v2.0, 12/7/2013 
Title page:  version and date updated 
Table of Contents:  added Appendix 6, Summary of Changes (q.v.) 
Section 6.4.2.1 (page 26):  updates to bone biopsy procedure 
Throughout:  minor typographyAmendment 2:  v3/0, 2/4/13 
Title page:  version and date updated 
Section 4.3, Exclusion Criterion #13 (page 20):  Patients requiring therapeutic 
anticoagulation are not eligible for this study. 
 
Amendment 3:  v3.1, 3/12/13 
Title page:  version and date updated 
Section 5.9:  inserted language required by the supporting drug company (Janssen 
Services LLC), regarding handling precautions for women of childbearing 
potential, pregnant, or lactating. 
Throughout:  minor typography 
 
Amendment 4:  v4.0, 4/21/13 
Throughout:  added Dose Escalation for all cohorts (formerly only cohort 3 pts) and 
Pharmacokinetic Analysis (not previously included) 
Title page:  version and date updated 
Exploratory Objectives (throughout):  response to dose escalation; mechanisms of 
resistance via pharmacokinetic analysis; pharmacokinetics of 1000mg b.i.d. 
dosing 
Section 6.4.2.1, Biopsy Procedure:  removed extraneous reference to anticoagulant 
therapy 
Section 6.6, Adverse Events:  Lab abnormalities will be captured as AEs if they are 
deemed clinically significant by the treating physician/clinician 
Section 7.3.3, Pharmacokinetics:  added 
Appendix 1, Schedule of Events:  Pharmacokinetics added at the Progression 
timepoint 
Throughout:  minor typographic and/or formatting corrections 
Amendment 5:  v5.0, 04/13/2015 
Title page:  version and date updated 
Section 5.5: updated drug interaction information for CYP2C8. 
Section 7:  removed Phosphorus (PO) from Lab studies; protocol text now matches 
Labs table in Section 6.4.1. 
Clarified SAE Notification to IRB and Janssen to “within 24 business hours.” 
Throughout:  minor typography 
Amendment 6:  v6.0, 09/10/2015 
 
6.7.4.1 Updated SAE reporting guideline to match CC-IRB reporting guidelines.  
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021

 
 
Clinical Study Protocol: PD Abiraterone acetate 
 
 
 
Confidential 
Page 69 of 69 
Section 4.2 Inclusion criteria 13 changed to say 2 lines of chemotherapy.  
 
 
 
 
 
7639
IRB Approved 
Document Release Date: 10/18/2017
Printed on 3/7/2021