A Phase II Study of Increased-Dose Abiraterone Acetate in Patients With Castration Resistant Prostate Cancer (CRPC)
Phase: PHASE2
Conditions: Castration Resistant Prostate Cancer
Sponsor: Terence Friedlander, MD

A Phase II Study of Increased-Dose Abiraterone Acetate in Patients with 
Castration Resistant Prostate Cancer (CRPC) 
Protocol Number:  CC#12551 
Study Drug:  Abiraterone Acetate 
Version Number:  7.0 
Version Date:  February 17, 2014 
IND Number:  115,408 
Study Chair (Sponsor-Investigator): 
Terence W. Friedlander M.D. 
Assistant Clinical Professor of Medicine 
Genitourinary Medical Oncology Program 
UCSF Helen Diller Family Comprehensive Cancer Center 
 
 
 
 
 
 
terence.friedlander@ucsf.edu 
Co-Investigators: 
Eric J. Small, M.D. 
Charles J Ryan M.D. 
Lawrence Fong, M.D. 
Amy Lin, M.D. 
Andrew Hsieh, M.D. 
Rahul Aggarwal, M.D. 
Won Kim, M.D. 
Statistician: 
Vivian Weinberg, PhD 
Revision History 
Version 6.0 
09-20-2013
Version 5.0 
04-29-13
Version 4.0 
11-30-12
Version 3.0 
05-30-12
Version 2.0 
02-24-12
Version 1.0 
11-09-11
NCT Number:01637402 

Version date: 02-17-2014 
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Phase 2:  Abiraterone Acetate 
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Protocol Signature Page 
Protocol No.: 7.0 
Version Date: 2-17-2014 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee
(PRC), Committee on Human Research (CHR), and Data Safety Monitoring Committee (DSMC).
2. I will conduct the study in accordance with applicable CHR requirements, Federal regulations,
and state and local laws to maintain the protection of the rights and welfare of study participants.
3. I certify that I, and the study staff, have received the requisite training to conduct this research
protocol.
4. I have read and understand the information in the Investigators‟ Brochure (or Manufacturer‟s
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the
www.clinicaltrials.gov website.
5. I agree to maintain adequate and accurate records in accordance with CHR policies, Federal,
state and local laws and regulations.
UCSF Principal Investigator / Study Chair 
Printed Name 
Signature 
Date 
Participating Site(s) 
PI:  Julie Graff, MD 
Oregon Health and Sciences University  
E-mail:  graffj@ohsu.edu
Principal Investigator 
Site 
Printed Name 
Signature 
Date 

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Phase 2:  Abiraterone Acetate 
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Study Schema 

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TABLE OF CONTENTS 
 STUDY SCHEMA ...................................................................................................................... 3 
1   BACKGROUND ................................................................................................................... 5 
2   OBJECTIVES ..................................................................................................................... 17 
3   STUDY DESIGN ................................................................................................................. 17 
4   DRUG INFORMATION ....................................................................................................... 23 
5   STUDY PROCEDURES AND OBSERVATIONS ................................................................ 26 
6   CORRELATIVE STUDIES .................................................................................................. 38 
7   STATISTICAL CONSIDERATIONS  .................................................................................. 39 
8 CRITERIA FOR RESPONSE/PROGRESSION .................................................................. 43 
9 REPORTING AND DOCUMENTATION OF ADVERSE EVENTS ...................................... 45 
10 DATA AND SAFETY MONITORING PLAN ........................................................................ 50 
11 STUDY MANAGEMENT ..................................................................................................... 52 
12  REFERENCES ................................................................................................................... 57 
APPENDIX A: COMMON TOXICITY CRITERIA ...................................................................... 59 
APPENDIX B: RECIST CRITERIA ........................................................................................... 60 
APPENDIX C: PROSTATE CANCER WORKING GROUP 2 CRITERIA ................................. 63 
APPENDIX D:  DRUG DIARIES ............................................................................................... 65 
APPENDIX E:  PROHIBITED CONCOMMITANT MEDICATIONS ........................................... 68 

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1. BACKGROUND
1.1. 
Hormonal Therapy in Prostate Cancer 
Prostate cancer is the second most common cancer in men representing approximately 30% of 
all cancers diagnosed in men. When confined to the prostate gland the disease is curable with 
local therapy. However approximately 50% of men fail local therapy and develop incurable 
metastatic disease. Androgen deprivation therapy (ADT) remains the mainstay of treatment, not 
only for advanced disease but also in the adjuvant and in certain neoadjuvant settings. ADT 
lowers circulating testosterone levels, induces a remission in 80 to 90% of patients with advanced 
disease, and results in a median progression-free survival of 12 to 33 months, at which time a 
castration resistant phenotype usually emerges. This accounts for the median overall survival of 
23 to 37 months from the initiation of androgen deprivation. 
1.2. 
  Mechanisms of Prostate Cancer Growth Despite ADT 
Androgen deprivation can be achieved surgically with orchiectomy, or by drug treatment.  Current 
approaches to ADT utilize luteinizing hormone releasing hormone (LHRH) agonists.  These act 
by continuous stimulation of the anterior pituitary resulting in inhibition of luteinizing hormone (LH) 
secretion, and hence a fall in testicular production of testosterone. Although ADT is clinically 
effective in the majority of patients, the adrenal cortex remains active and produces multiple 
androgens including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) 
and androstenedione. While not as potent as testosterone or dihydrotestosterone, these 
androgens nonetheless can function as weak agonists for the wild type AR and can stimulate 
mutant AR resulting in cell growth. Similarly, these androgens may be peripherally converted to 
dihydrotestosterone, a potent stimulator for AR, by the enzyme 5a reductase1,2.  
Studies have shown that adrenal androgens represent an important alternative source of 
stimulation in a significant proportion of prostate cancer patients. As much as 10% of baseline 
circulating testosterone remains in castrate men, due to the peripheral conversion of adrenal 
steroids to testosterone3. Increased levels of androgen receptor have been documented in CRPC 
cells and confer resistance to antiandrogens in prostate cancer xenograft models4. This 
amplification is hypothesized to result in amplified signal output from circulating low levels of 
adrenal androgens and suggests a role for agents that target the adrenal androgen synthesis 
pathway. 
At the same time androgen production by tumor cells themselves has been postulated to lead to 
increased levels of androgens in the tumor microenvironment. CRPC cells express higher levels 
of enzymes responsible for androgen synthesis, and androgen levels are higher in metastatic 
CRPC biopsies than in circulation5. Using agents that target both this intracrine androgen 
production as well as systemic androgen production therefore have the potential to slow CRPC 
growth.  
1.3. 
Adrenal Androgens in Prostate Cancer 
Prior studies have shown that suppression of adrenal androgen synthesis can slow the growth of 
CRPC. Ketoconazole is an orally available azole antifungal agent that inhibits the side chain 
cleavage enzyme responsible for the conversion of cholesterol to pregnenolone, a necessary 

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step in the production of all androgens. Ketoconazole has been shown to suppress DHEA, 
DHEAS and androstenedione following one month of therapy, and has been shown to have 
modest antitumor activity in patients who have progressed on combined LHRH agonist and 
antiandrogen therapy6.  Approximately 30% of patients enrolled on CALGB 9583, a randomized 
phase III trial of antiandrogen withdrawal (AAWD) alone versus high-dose 
ketoconazole/hydrocortisone experienced a 50% or greater PSA decline. A statistically significant 
(p=0.0001) increase in DHEAS and androstenedione was noted at the time of progression on 
ketoconazole suggesting that, over time, this drug loses its ability to inhibit adrenal androgen 
synthesis.  
Another limitation of ketoconazole, however, is the fact that it is an unselective inhibitor of 
CYP450 enzymes. It inhibits cholesterol side chain cleavage and 11-hydroxylation7 as well as 
CYP17 activities. The result of this lack of specificity is an almost universal requirement for 
corticosteroid replacement in patients leading to increased cost, potential for morbidity and 
difficulty with compliance. Abiraterone Acetate was developed specifically to address this need. 
1.3.1. The Adrenal Steroid Synthesis Pathway 
The adrenal steroid synthesis pathway is shown below in Figure 1. The enzyme complexes 
inhibited by Abiraterone Acetate and ketoconazole, are shown. Ketoconazole‟s principal 
mechanism of action is blockade of the cholesterol side chain cleavage enzyme as well as 
11-beta hydroxylase, as shown, whereas Abiraterone Acetate inhibits the CYP 17A1 complex
of enzymes, with dual c17 lyase and 17, 20 hydroxylase activity. As the figure demonstrates,
the end result of inhibition is a reduction of adrenal androgen production.
Figure 1: The adrenal steroid synthesis pathway 

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1.4. 
  Abiraterone Acetate (JNJ212082). 
Abiraterone Acetate (JNJ212082, previously known as CB7630) is the 3-acetate and a prodrug of 
JNJ-589485 (previously known as CB7598) suitable for oral administration.  Abiraterone Acetate 
[JNJ-589485, 17-(3-pyridyl) androsta-5,16-dien-3β-ol] was developed as a highly specific 
steroidal inhibitor of CYP17 (17a-hydroxylase/C17,20-lyase), with two important enzymatic 
activities in the synthesis of testosterone, based on the observation that nonsteroidal 3-pyridyl 
esters had improved selectivity for inhibition of 17α-hydroxylase/C17,20- lyase.8 JNJ-589485 is a
potent inhibitor with an apparent inhibition constant of 0.5 nM.  
The chemical nomenclature of JNJ212082 is 3β-acetoxy-17-(3-pyridyl) androsta-5,16-diene; its 
empirical formula is C26H33NO2.  It has a molecular weight of 391.55.  Once absorbed after oral 
administration, JNJ212082 is rapidly converted to the active form, JNJ-589485 (Figure 2).  JNJ-
589485 was the predominant, if not the only form of Abiraterone Acetate detected in blood both in 
preclinical studies and in previously conducted clinical studies.  
Abiraterone Acetate (1000 mg) is FDA approved for use with prednisone for metastatic 
castration-resistant prostate cancer following docetaxel.  It is used in patients whose disease has 
not gotten better with other chemotherapy or hormone therapy.   
1.5. 
Rationale For Using Abiraterone Acetate in Prostate Cancer 
The major limitation of therapy with ketoconazole is the development of resistance to the therapy 
over time, the high rate of intolerability due to gastrointestinal toxicities, and the multiple drug 
interactions that limit its use in patients with comorbidities. In addition, therapy with ketoconazole 
requires the administration of 6 ketoconazole tablets daily as well as three tablets of 
hydrocortisone daily for glucocorticoid replacement. As Abiraterone Acetate is administered as 4 
tablets once daily and does not have significant drug-drug interactions, it represents a significant 
advance in the management of androgen independent prostate cancer and a desirable 
alternative to ketoconazole. 
Figure 2. 
Prodrug Abiraterone Acetate is converted to Abiraterone after absorption. 
1.6. 
Clinical Data with Abiraterone Acetate. 
To determine if inhibition of 17-alpha-hydroxylase/C17,20 lyase could indeed suppress adrenal 
testosterone production in human as predicted from mechanism of action and animal models, 
Phase 1 exploratory studies of JNJ212082 were conducted in castrated or noncastrated patients 
with prostate cancer.  An overview of the three initial Phase 1 studies is provided as well as an 
overview of subsequent studies. In the first series of phase 1 studies a total of 26 patients were 

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treated with doses ranging from 10 to 800 mg/d. Overall, the results of these studies showed that 
JNJ212082 was safe and well tolerated.  At 500 and 800 mg/d either as single dose or as 
consecutive daily doses, significant decreases in circulating testosterone were observed.  The 
effects of JNJ212082 on glucocorticoid and mineralocorticoid levels were also investigated 
especially in patients receiving 12-day continuous dosing at 500 and 800 mg/d.  There were no 
clear clinical signs of mineralocorticoid excess or glucocorticoid insufficiency.  In this multiple-
dose study, basal levels of cortisol were within normal limits, but short Synacthen tests with 
standard doses of adrenocorticotropic hormone (ACTH) on Day 11 showed diminished peak 
cortisol levels at 30 minutes when compared with those in pretreatment test.  However, the peak 
responses that were below the 500 nmol/L (18 µg/dL) normal threshold were observed only in 
five of the six patients (two at 500 and three at 800 mg/d dose levels).  The clinical relevance of 
abnormal ACTH stimulation test in patients receiving JNJ212082 is unknown.  Results from these 
Phase 1 studies were published in the British Journal of Cancer9. 
A second Phase 1/2 was then performed in which a total of 21 patients were treated with in a 
dose escalation fashion ranging from 250 to 2000 mg/d10.  A total of 3 patients were treated at the 
maximum dose of 2,000 mg/d and no treatment related grade 3 or 4 toxicities were observed in 
any patient. Two patients at the 2,000 mg/d dose experienced Grade 1-2 hypertension, two 
experienced Grade 1-2 hyperkalemia, and one experienced Grade 1-2 peripheral edema.  
Because a plateau of endocrine effects was seen at 750 mg/d, the 1000 mg/d dose was chosen 
as the recommended phase 2 dose. An expansion to a phase II study was then performed at the 
1,000 mg/d dose in an additional 33 men. A PSA decline of ≥ 50% was observed in 28 (67%) of 
42 Phase I/II patients treated at 1,000 mg/d. Radiographic partial responses by RECIST criteria 
were seen in 9 (37.5%) of 24 phase II patients with measurable disease. Importantly, the addition 
of dexamethasone at disease progression reversed resistance in 33% of patients regardless of 
prior treatment with dexamethasone. 
Abiraterone Acetate was evaluated in a subsequent Phase I study in men with chemotherapy 
naïve CRPC11. A total of 33 men were enrolled, including 19 (58%) who had received prior 
ketoconazole. Fasted or fed cohorts were treated with Abiraterone Acetate doses of 250, 500, 
750, or 1,000 mg daily and single-dose pharmacokinetic analyses were performed before 
continuous daily dosing. Confirmed ≥ 50% PSA declines at week 12 were seen in 18 (55%) of 33 
patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 
patients without prior ketoconazole therapy. Substantial declines in circulating androgens and 
increases in mineralocorticoids were seen with all doses. No dose-limiting toxicities were 
observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the 
most frequent serious toxicities and responded to medical management. On the basis of 
evidence of clinical responses across several doses, maximization of the intended endocrinologic 
effects, and the favorable safety, dose escalation was ceased at 1,000 mg daily. 
A series of phase II study then evaluated Abiraterone Acetate in men with CRPC. In one study 33 
patients received Abiraterone Acetate 1,000 mg daily with prednisone 5 mg twice daily in 
continuous 28-day cycles12. Prednisone was added to mitigate mineralocorticoid excess which 
resulted in the hypokalemia and hypertension observed in the Phase I studies. A ≥50% PSA 
decline at week 12 was confirmed in 22/33 (67%) patients. PSA declines of ≥50% were seen in 
26/33 (79%) patients. PSA declines of any magnitude at 12 weeks were observed in 85% of 
patients. Undetectable PSA levels (≤0.1 ng/mL) occurred in two patients. Median time on therapy 
and time to PSA progression were 63 weeks and 16.3 months, respectively. Adverse events 
were typically grade 1/2 and consistent with prior published Abiraterone Acetate reports.  

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A second phase II study of 58 men with progressive metastatic CRPC who experienced 
treatment failure with docetaxel-based chemotherapy received Abiraterone Acetate 1,000 mg 
daily with prednisone 5 mg twice daily13. Twenty-seven (47%) patients had received prior 
ketoconazole. A ≥50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 
31 ketoconazole-naïve and seven (26%) of 27 ketoconazole-pretreated patients. Partial 
responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. 
Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days 
(95% CI, 82 to 200 days). The majority of adverse events were grade 1 to 2, and no Abiraterone 
Acetate-related grade 4 events were seen. 
A third phase II study evaluated Abiraterone Acetate in 42 patients who previously received 
docetaxel. PSA declines of ≥ 30%, ≥ 50% and ≥ 90% were seen in 68% (32 of 47), 51% (24 of 
47), and 15% (seven of 47) of patients, respectively. Partial responses (by RECIST) were 
reported in eight (27%) of 30 patients with measurable disease. Median time to PSA progression 
was 169 days (95% CI, 113 to 281 days). The median number of weeks on study was 24, and 12 
(25.5%) of 47 patients remained on study ≥ 48 weeks. 
Abiraterone Acetate was subsequently evaluated in COU-AA-301, a multicentered randomized, 
double-blind placebo controlled Phase 3 study14. In total 1195 men with CRPC who had 
previously received docetaxel were randomly assigned in a 2:1 fashion to received prednisone 
5mg twice daily plus either 1000 mg of Abiraterone Acetate (797 patients) or placebo (398 
patients). The primary end point was overall survival. After a median follow-up of 12.8 months, 
overall survival was longer in the Abiraterone Acetate–prednisone group than in the placebo–
prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 
0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded 
the preplanned criteria for study termination. All secondary end points, including time to PSA 
progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 
months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group.  
On the basis of this study, in April 28th, 2011 the United States Food and Drug Administration 
approved abiraterone acetate for use in combination with prednisone for the treatment of patients 
with metastatic CRPC who have received prior chemotherapy containing docetaxel. 
A second multicentered randomized double-blind placebo-controlled Phase III study, COU-AA-
302, is testing the effect of Abiraterone Acetate 1000mg daily plus prednisone 5mg bid in men 
with CRPC who have not yet received chemotherapy, with progression-free and overall survival 
as co-primary endpoints. This study is currently ongoing. 
1.7. 
Clinical Safety Data 
Over 1400 men with CRPC have been treated in the aforementioned studies, with the vast 
majority of patients having received the 1,000 mg/d dose. Overall the most common adverse 
events (≥5%, all grades) observed in clinical studies were joint swelling or discomfort, 
hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, 
hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract 
infection. In that phase III study common adverse events in both groups were back pain (30% in 
the Abiraterone Acetate group and 33% in the placebo group), nausea (30% and 32%, 
respectively), constipation (26% and 31%), bone pain (25% and 28%), and arthralgia (27% and 
23%). Most of these events were grade 1 or 2. Urinary tract infection was more frequent in the 
Abiraterone Acetate group (12%, vs. 7% in the placebo group; P=0.02); these infections were 

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also primarily grade 1 or 2 events. Adverse events resulting in treatment discontinuation occurred 
with similar frequency in the Abiraterone Acetate and placebo groups (19% and 23%, 
respectively; P=0.09). The incidence of adverse events leading to dose modification or 
interruption was also similar in the two groups. Adverse events associated with elevated 
mineralocorticoid levels due to CYP17 blockade (fluid retention and edema, hypokalemia, and 
hypertension) were observed in the phase I and II studies and were treated with aldosterone 
antagonists, potassium supplementation, and concurrent administration of corticosteroids (see 
section 1.9). In the phase III study the incidence of fluid retention and edema was higher in the 
Abiraterone Acetate group (31%, vs. 22% in the placebo group; P=0.04). Grade 1 or 2 peripheral 
edema accounted for most of these events. Hypokalemia also occurred in a higher proportion of 
patients in the Abiraterone Acetate group (17%, vs. 8% in the placebo group; P<0.001).  
In the phase III study cardiac events (primarily grade 1 or 2) occurred at a higher rate in the 
Abiraterone Acetate group than in the placebo group (13% vs. 11%, P=0.14), but the difference 
was not significant. The most frequently reported cardiac events were tachycardia (3% in the 
Abiraterone Acetate group and 2% in the placebo group, P=0.22) and atrial fibrillation (2% and 
1%, respectively; P=0.29). All tachycardia events were grade 1 or 2; atrial fibrillation events were 
grade 3 or lower. Despite the slightly higher incidence of cardiac events in the Abiraterone 
Acetate group than in the placebo group, there was no significant increase in fatal cardiac events 
in the Abiraterone Acetate group (1.1%, vs. 1.3% in the placebo group). One death associated 
with arrythmia and one patient with sudden death were observed on the Abiraterone Acetate arm, 
while none were observed on the placebo arm.  
In the phase III study a grade 4 elevation in an aminotransferase level early in the study led to a 
protocol amendment specifying more frequent monitoring with liver-function tests during the first 
12 weeks of treatment. Overall, however, abnormalities in liver-function tests occurred at a similar 
frequency in the Abiraterone Acetate and placebo groups, including changes of any grade in 
liver-function tests (10% and 8%, respectively), grade 3 or 4 changes in liver-function tests (3.5% 
and 3.0%), grade 3 or 4 elevations in aspartate aminotransferase levels (1.4% and 1.6%), grade 
3 or 4 elevations in alanine aminotransferase levels (1.0% and 1.1%), and grade 4 elevations in 
aminotransferase levels (0.3% and 0.5%). Across all studies elevations hepatotoxicity was 
observed in 2.3% of patients typically during the first 3 months of treatment. Elevations in 
AST/ALT returned to normal upon drug discontinuation. 
Overall in the Phase III study grade 3-4 events were rare; compared to placebo-treated patients, 
patients on the Phase III studied treated with Abiraterone Acetate were more likely to experience 
Grade 3-4 hypertension (1.3% vs. 0.3%), edema (1.9% vs. 0.8%), urinary tract infection (2.1% vs. 
0.5%), cardiac failure (1.9% vs. 0.3%), elevated AST (2.1% vs 1.5%), hypokalemia (5.3% vs 1%), 
hypophosphatemia (7.2% vs 5.8%) and elevated ALT (1.4% vs 0.8%). No individual grade 4 
adverse events occurred in 2% or more of patients in either treatment group. 
In the Phase III study a total of 11% of patients in the Abiraterone Acetate group and 13% of 
patients in the placebo group died within 30 days after the last dose of study medication, primarily 
as a result of disease progression. A lower proportion of patients in the Abiraterone Acetate 
group than in the placebo group had an adverse event that resulted in death (12% vs. 15%). 
1.8. 
Clinical Pharmacokinetics 
Blood specimens from phase 1 studies were analyzed for JNJ-589485.  The pharmacokinetic 
parameters all show considerable variability between patients and are presented in Table 1.  The 

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mean Tmax was 2.70 hours (+ Std Dev 2.71) with a mean elimination half-life of 27.6 hours (+ Std 
Dev 20.17). A range of up to 10-fold in AUC was seen for a given dose. The level of interpatient 
variability made analysis of dose-dependent pharmacokinetic relationships difficult.  Further 
investigation is required in clinical trials. Adrenal metabolite analysis showed inhibition of CPY17 
even at low doses of Abiraterone Acetate and a compensatory increase of corticosterone was 
apparent at all dose levels tested. 
When administered with food that had high-fat content, drug exposure was signiﬁcantly increased 
(by 4.4-fold) compared with fasting administration (P=0.049; Fig 3D). The variability between fed 
patients was comparable to that observed between fasted patients.  There was no signiﬁcant 
increase in Cmax, but absorption was signiﬁcantly extended after food. Based on these results 
and for consistency in absorption, in all subsequent studies of Abiraterone Acetate patients have 
been instructed to take orally at least 2 hours after a meal or 1 hour before a meal any time up to 
10 pm every day. 
The maximum dose of abiraterone acetate used in pharmacokinetic studies is 2,000 mg/d. Up to 
2.5 fold variations in AUC were observed at 750 mg/d and 2,000 mg/d cohorts. Figure 3 
demonstrates that despite interpatient variability overall both the AUC and Cmax appear to 
increase with increasing dose of abiraterone acetate.  The terminal half life of the 1000mg dose 
of abiraterone acetate is 14.4 hours. 

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Table 1: Summary of Pharmacokinetic Data for JNJ212082 Measured as JNJ-589485 in Plasma
Patient 
Dose 
(mg/m2)
AUC 
M.h
Cmax 
M
T max 
H 
T1/2
h 
T1/2
h 
Kabs
H 
1 
10 
ND 
ND 
ND 
ND 
ND 
ND 
2 
10 
ND 
0.001 
2 
ND 
ND 
ND 
3 
10 
ND 
0.018 
11 
ND 
ND 
ND 
4 
30 
ND 
ND 
ND 
ND 
ND 
ND 
5 
30 
ND 
0.004 
4 
ND 
ND 
ND 
6 
30 
ND 
0.006 
1 
ND 
ND 
ND 
7 
100 
0.15 
0.012 
13 
6.5 
ND 
6.5 
8 
100 
0.09 
0.011 
0.16 
0.97 
26.5 
0.03 
9 
100 
0.12 
0.019 
3.7 
2.0 
28 
1.8 
10 
200 
0.39 
0.061 
2.8 
1.59 
25.8 
3.87 
11 
500 
0.25 
0.063 
0.8 
0.28 
29 
0.01 
12 
500 
1.68 
0.139 
3.7 
1.83 
21 
1.8 
13 
500 
0.73 
0.06 
3.6 
1.73 
74 
1.71 
14 
500 
0.67 
0.066 
4 
1.43 
18 
1.41 
15 
500 
0.42 
0.077 
2 
0.29 
13.4 
1.00 
16 
500 
1.38 
0.167 
2.7 
0.05 
13.3 
1.15 
17 
200 
0.23 
0.037 
0.69 
1.49 
28 
0.03 
18 
500 
1.23 
0.054 
1.7 
0.19 
14.6 
0.3 
19 
500 
1.101 
0.183 
1.51 
0.71 
14 
0.7 
20 
500 
2.08 
0.30 
1.41 
1.59 
24 
0.12 
21 
500 
3.54 
0.62 
1.70 
1.07 
23.2 
0.82 
22 
500 
0.34 
0.07 
2.30 
0.79 
12.0 
0.80 
23 
500 
NE 
NE 
NE 
NE 
NE 
NE 
24 
800 
11.66 
1.19 
3.02 
1.32 
87 
1.34 
25 
800 
2.32 
0.43 
1.20 
0.45 
19.9 
0.45 
26 
800 
2.84 
0.18 
3.10 
1.73 
26.2 
1.82 
Details of patients: 
PT 1 - 16: single dose study in castrate males 
PT 17 - 20: single dose in non-castrate males 
PT 21 - 26: multi-dose study in non-castrate males 
Abbreviations: 
NE: Not evaluated due to problems with the assay; ND: Not detectable, plasma concentrations too allow to 
permit estimation of the   pharmacokinetic behaviour of the drug; AUC: Area under the concentration time 
curve; Cmax: maximum concentration; Tmax: time to maximum concentration, T1/2: Initial half-life, T1/2: terminal 
half life; Kabs: absorption rate constant. 

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Figure 3: Additional Pharmacokinetic Data for JNJ212082 Measured as JNJ-589485 in Plasma
Figure 3: Pharmacokinetics of Abiraterone Acetate. (A) Area under the concentration-time curve versus 
dose in fasted patients; (B) maximum concentration (Cmax) versus dose in fasted patients 
1.9. 
Concurrent Prednisone 
Reduced cortisol levels induced by blockade of CYP17A1 lead to a compensatory ACTH surge 
and thereby result in the hypertension, hypokalemia, and fluid retention observed in the Phase 1 
and 2 studies.  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 improved symptoms of fatigue 
and tolerability of Abiraterone Acetate in Phase 2 studies, 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 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 or as a monotherapy for palliation of symptoms.  The use of concurrently 
administered prednisone was evaluated in the COU-AA-301 phase III study and was determined 
to be safe and effective as discussed in section 1.7.  
1.10. Hypotheses regarding resistance to adrenal targeted therapies 
Resistance to Abiraterone Acetate is hypothesized to develop due to an inability over time of 
Abiraterone Acetate to suppress androgen synthesis, resulting in increasing levels of androgens 
within tumors and disease progression. This hypothesis is supported by multiple lines of 
evidence. First, pretreatment androgen levels are associated with the likelihood of response to 
Abiraterone Acetate15, suggesting that CRPC tumors rely on androgen signaling for growth and 
survival.  Second, molecular analysis of CRPC tumors has shown that enzymes regulating 
androgen synthesis are upregulated compared to benign tissue, and that intratumoral androgen 
levels are elevated16, suggesting that suppressing both systemic and local androgen production 

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in the tumor microenvironment may be necessary to induce a clinical response. Third, circulating 
androgen levels are known to rise at the time of clinical progression on ketoconazole, an agent 
similar to Abiraterone Acetate, suggesting that increases in androgen signaling may lead to 
progression of disease.17 Fourth, the addition of dexamethasone at the time of disease 
progression on Abiraterone Acetate has been shown to induce second responses10, suggesting 
possibly that manipulation of the hormonal milieu even at the time of disease progression on 
Abiraterone Acetate has the potential to reverse Abiraterone Acetate resistance.  Lastly, while a 
pharmacodynamic study of Abiraterone Acetate in men with CRPC did not show consistent rises 
in circulating androgen levels and the time of disease progression18, intratumor androgen levels 
were not assayed and therefore androgen levels within CRPC tumors at the time of progression 
on Abiraterone Acetate are unknown. Similarly, the small total number of patients (n=14) and the 
4 different dosing schedules investigated in this initial pharmacodynamic study greatly limits the 
statistical power of this observation. Taken together this evidence suggests that further reduction 
in androgen synthesis has the potential to slow tumor growth and result in a second response to 
Abiraterone Acetate therapy.  
1.11. Rationale for using dose increased Abiraterone Acetate at the time of clinical 
progression 
Intratumoral androgen levels are hypothesized to increase at the time of clinical progression, and 
pharmacokinetic studies suggest that an increased dose of Abiraterone Acetate can result in a 
higher exposure of CRPC to drug. 
Elevated dose therapy is given at disease progression as opposed the outset of therapy for a 
number of reasons: 

Standard dose Abiraterone Acetate appears to be an effective therapy for the vast
majority of men with CRPC not yet treated with chemotherapy, with close to 80%
response rate and a median time to progression of 11.5 months in phase 2 testing.
Therefore most subjects men stand to benefit clinically from a standard dose „run-in‟
period.

Dose increase at the time of resistance to standard dose therapy will allow for better
characterization of the biology of Abiraterone Acetate resistance both by analysis of
hormone levels at the time of initial resistance, and characterization of hormone and PSA
responses to increased dose.

While safe and well tolerated at all dosing levels in phase 1 testing, increased dose
Abiraterone Acetate has not been tested in large numbers of subjects, and therefore
increased dose at the time of initial therapy could place some subjects at risk of
unnecessary toxicity.

As the terminal half-life of the 1000mg daily dose is 14.4 hours, a dose of 1000mg BID
(q12 hours)  is chosen, as this dose is likely to result in consistently higher abiraterone
levels. 4 x 250mg tablets BID is also expected to be easier to take than 8 x 250mg tablets
at once.

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1.12. Rationale for using PSA response as the primary endpoint 
PSA response defined as a ≥30% PSA decline from baseline after 12 weeks of elevated dose 
therapy will be used as a primary endpoint in this study. Although PSA is not a surrogate for 
survival19, there exists no better biomarker that is easily measured, widely used in clinical 
practice, and not subject to interobserver bias. Moreover, while objective measures (bone scan, 
CT scan) have been used to define disease progression in Phase III clinical studies of 
Abiraterone Acetate, it is likely that treatment resistance develops long before disease 
progression is radiographically apparent, and in the majority of cases resistance is heralded by a 
rise in the PSA. Similarly, it is expected that most clinicians will use PSA response to make 
decisions about when to stop treating patients with Abiraterone Acetate. Lastly, PSA response 
endpoints, as described in this study, have been recently endorsed as suggested outcome 
measures by the Prostate Cancer Clinical Trials Working Group20. Therefore PSA response will 
be used in this study as an endpoint. 
1.13. Rationale for this study 
Determination of the mechanisms of resistance to standard-dose Abiraterone Acetate is 
important in this patient population. Observational data suggests that increased androgen levels 
may allow CRPC to grow despite androgen synthesis inhibitor therapy. This study will aid in the 
understanding of resistance to Abiraterone Acetate, and simultaneously test whether resistance 
may be overcome via an increased dose. The study will also allow for a pharmacokinetic and 
pharmacodynamic understanding of resistance and may aid in allowing clinicians to risk-stratify 
patients for appropriately dosed therapy. 
This is an investigator initiated study. Janssen Services will be supporting the study by supplying 
Abiraterone Acetate and study funding. 
1.14. Mechanisms of Resistance 
1.14.1. Circulating Tumor Cell and Metastatic Biopsy, and Pharmacogenetic Analysis 
Resistance to Abiraterone Acetate is hypothesized to be due to a failure over time of 
abiraterone to inhibit androgen synthesis leading to a rise in intratumoral androgen levels 
and progression of disease. Mechanisms of increased synthesis include amplification of 
CYP17A1 and other genes in the androgen synthesis pathway, changes in CYP17A1 
gene methylation leading to increased expression, or point mutations impairing the ability 
of Abiraterone Acetate to bind to its CYP17A1 substrate. Other mechanisms include AR 
amplification, over-expression, or loss of negative regulators of AR.  
In order to discover the genetic events associated with treatment resistance, genomic 
analysis of circulating tumor cells (CTCs) and metastatic CRPC biopsies are techniques 
which offer the ability to analyze in real-time genomic changes in pathways associated 
with resistance. Quantitative CTC counting has demonstrated promise as a biomarker 
of response in men with CRPC treated with abiraterone and with chemotherapy, and 
qualitative analysis of CTCs offers the potential to interrogate genomic changes 
occurring in the androgen synthesis pathway in men treated with abiraterone.  
Because CTC analysis is exploratory, biopsy of metastatic tissue offers a similar 
potential to evaluate changes in methylation as well as in the expression of CYP17A1 
and other androgen synthesis genes, the androgen receptor (AR) and coregulators, 

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and other genes implicated in resistance to Abiraterone. Experience in CRPC has 
demonstrated that it is possible and feasible to collect metastatic biopsies prior to and 
on therapy. Currently, based on a Phase II trial that uses microarray-results from 
radiologically-guided therapies to determine AR activity so as to guide therapy, the 
technical success rate over the past 35 biopsy procedures is 74%. Thus, for the 
proposed trial, a similar if not improved success rate is anticipated. Microarray 
analysis of biopsies, in combination with exploratory CTC analysis, therefore has the 
potential to generate a wealth of data and allow for the discovery of both hypothesized 
and novel mechanisms of resistance to Abiraterone. 
1.14.2. Pharmacogenetic Analysis 
Signaling mediated by steroid hormone activation of the AR is suspected to be not 
only a pivotal event leading to the initial development of prostate cancer, but also 
critical in the progression of disease despite androgen deprivation.  The CYP17A1 
gene is located on chromosome 10q24.3 and encodes the cytochrome P450c17a, 
which is responsible for 17 –alpha-hydroxylase and 17-20 lyase enzymatic activity, 
key steps in the development of androgens (See Fig 1).  Several benign conditions 
associated with androgen excess including male pattern baldness and polycystic 
ovaries in women have been associated with a variant allele of CYP17A1, A2. The 
CYP17A1 A2 allele polymorphism results from a single base pair substitution (-
34T>G) located in the 5‟ untranslated region upstream of the initiation site. The net 
effect of this polymorphism is the creation of an additional Sp-1 type promoter site, 
which is hypothesized to result in increased transcription of the CYP17A1 gene 
leading to higher androgen levels.  The A2 allele is present in approximately 56% of 
the Caucasian population, and 13-15% are homozygous for the A2 allele21.  
A series of studies have associated polymorphisms of CYP17A1 with risk of prostate 
cancer incidence and mortality. Stanford and colleagues, in a population-based study 
of incident prostate cancer, demonstrated that men with a family history of prostate 
cancer who are homozygous for the A2 allele of CYP17A1 have a 19-fold increased 
risk of prostate cancer22. Subsequently, Hamada and colleagues demonstrated that 
the presence of a polymorphism in the promoter region of the CYP17A1 gene is 
associated with survival in patients with CRPC regardless of the therapy given. In this 
analysis, the median survival from the time of diagnosis in patients with the variant 
allele (n=126) was 8.9 years versus 6.7 years in the patients with the A1 (reference) 
allele (P=0.04).23 Although potentially contaminated by lead-time bias, these results 
collectively suggest that CYP17A1 polymorphisms deserve further study in the CRPC 
setting, in particular because CYP17A1 is now receiving considerable interest as a 
drug target. Interestingly, the two studies diverge somewhat in their conclusions 
suggesting that the onset of the disease may be increased by the presence of the 
SNP (potentially due to tumor promotion by higher androgen levels) yet in patients 
with prostate cancer the SNP may be protective (due to the effectiveness of androgen 
deprivation therapy compared to other approaches). Regardless, these studies did not 
incorporate specific CYP17A1 inhibitors and did not report differences in androgen 
levels.  
Analysis of germline CYP17A1 polymorphisms may therefore aid both in the 
understanding of primary resistance to adrenal androgen targeted therapies such as 
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resistance in men who have experienced a response to Abiraterone Acetate followed 
by disease progression. 
2. OBJECTIVES
2.1. 
Primary Objective 
To determine the efficacy of increased dose Abiraterone Acetate for patients who 
experienced disease progression following standard dose abiraterone acetate therapy. 
Primary endpoint is PSA response of at least 30% decline by 12 weeks. 
2.2. 
Secondary Objectives 

To evaluate the overall safety and tolerability of therapy with increased-dose Abiraterone
Acetate.

To determine the time to PSA progression and progression free survival (PFS) for
patients treated with increased dose Abiraterone Acetate.

To measure the pharmacokinetics of Abiraterone Acetate at the initiation of standard
dose therapy, at the time of initial disease progression, after the initiation of increased-
dose Abiraterone Acetate, and at the time of disease progression on increased-dose
therapy.

Relationship of circulating androgen levels to increased dose Abiraterone Acetate and
PSA decline.
2.3. 
Exploratory Objectives 

To evaluate the association between single-nucleotide polymorphisms within enzymes
inhibited by Abiraterone Acetate and response to standard-dose and elevated-dose
therapy.

To evaluate whether resistance to Abiraterone Acetate is mediated by increased AR
signaling, by measuring changes in the androgen receptor (AR) expression signature
from metastatic biopsies at the initiation of standard dose therapy and at the time of initial
progression.

To evaluate whether resistance to Abiraterone Acetate is mediated by increased
intratumoral androgen synthesis, by measuring CYP17A1 and androgen synthesis
methylation status in metastatic biopsies and in circulating tumor cells (CTCs) taken at
the initiation of standard dose therapy and at the time of initial progression.
3. STUDY DESIGN
3.1. 
Study Design 
This is a phase II multicenter trial of Abiraterone Acetate in patients with progressive prostate 
cancer despite androgen deprivation with a particular focus on the pharmacokinetic, 
pharmacodynamic, and pharmacogenomic events occurring at the time of apparent drug 
resistance. All eligible patients will have baseline (prior to taking the first dose of Abiraterone 
Acetate 1000mg/daily) measures of routine clinical variables along with measurements of 
baseline and treatment related changes in testosterone, androgen, and endocrine levels, 
genotyping of SNPs in the selected enzymes known to be directly inhibited by Abiraterone 
Acetate, and collection of circulating tumor cells. All patients will be requested to consent for 

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biopsies which will be performed prior to treatment and at the time of disease progression on 
standard dose Abiraterone Acetate therapy.  These biopsies will be analyzed for expression of an 
AR-signature as well as for microarray analysis to explore changes in methylation, and 
expression of CYP17A1 and other androgen synthesis genes.  
Subjects will then begin daily oral therapy with Abiraterone Acetate 1000mg po daily with 
physiologic prednisone 5mg BID replacement. No food should be consumed for at least 2 hours 
before the dose of Abiraterone Acetate and for at least 1 hour after the dose of Abiraterone 
Acetate is taken. PSA will be followed monthly.  Abiraterone Acetate will be supplied by Janssen 
Services.  At the end of the first month, the third month, and then every three months thereafter, 
Abiraterone Acetate, testosterone, and androgen levels will be followed. Subjects whose disease 
is not sensitive to Abiraterone Acetate and do not achieve any PSA decline at 12 weeks will be 
taken off study. At the time of progression (defined by RECIST criteria OR by the Prostate 
Cancer Working Group 2 (PCWG) criteria as a 25% increase in PSA above the nadir and an 
increase in the absolute value PSA of at least 2ng/dl or back to baseline confirmed at least 2 
weeks afterward) for subjects who achieved any initial PSA decline (referred to as Progressive 
Disease (PD) #1), subjects will begin taking Abiraterone Acetate 1000 mg po BID (q12 
hours). Patients will continue to take prednisone 5mg BID and will continue taking the 
combination of elevated-dose abiraterone and prednisone for at least 12 weeks, which will be the 
first point at which evaluation for PD#2 will be made. If PD#2 occurs at 12 weeks or at any point 
thereafter subjects will be withdrawn from the study.  While 1000 mg po BID is not the FDA 
recommended dose, it is the dose to be investigated in this study.  
3.2. 
Rationale for Selection of this Patient Population 
Patients with progressive prostate cancer despite castrate levels of testosterone in whom 
chemotherapy is not felt to be indicated yet are selected for this trial. There are few effective 
options for this population; these include, among others, ketoconazole, diethylstilbestrol, and 
antiandrogens. None of these options are curative, and only ~20-30% of men will have any 
significant clinical response to agents. Most men who experience PSA progression after a trial of 
these agents will require treatment with chemotherapy, which notably brings risks of 
myelosuppression, neurologic toxicity, and impairments in quality of life.  
Abiraterone Acetate with corticosteroid replacement has been shown to be clinically effective in 
multiple phase II studies in men with chemotherapy-naïve CRPC, with PSA progression free 
survival ranging from 24-63 weeks. It prolongs survival in men with CRPC previously treated with 
chemotherapy, and currently a multinational randomized placebo controlled Phase III study is 
evaluating the potential benefit of Abiraterone Acetate in men with CRPC who have not received 
chemotherapy. This patient population therefore has the potential to derive benefit from treatment 
with Abiraterone Acetate.  
Increasing the dose of Abiraterone Acetate at the time of disease progression is expected to 
“rescue” a proportion of men failing standard dose Abiraterone Acetate therapy, and thus will 
spare these patients the toxicities that come with most chemotherapeutic regimens.  
Only patients with metastatic progressive castration resistant disease (as evidenced by RECIST 
criteria or by Prostate Cancer Working Group 2 criteria20) for bony disease will be included in this 
study to render the population uniform. It will also potentially allow for a higher yield in terms of 
tumor biopsy and CTC collection.  

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3.3 Population Base and Recruitment: 
Patients will be recruited through the Urologic Oncology Program.  Members of all ethnic groups 
are eligible for this trial. The following table summarizes the ethnicity of the Bay Area prostate 
cancer incidence and the ethnic breakdown of new prostate cancer cases seen at UCSF in 2006. 
Table 2 
All Races 
White/Non
-Hispanic
Black 
Hispanic 
Asian/ 
Pacific Is. 
Other/ 
Unknown 
*Bay Area
Population Males
Only (2006)
2,142,518 
(100%) 
1,010,225 
(47%) 
170,506 
(8%) 
451,505 
(21%) 
444,944 
(21%) 
8,077 
(0.41%) 
*Bay Area
Prostate Cancer
Incidence (2006)
2,872 
(100%) 
1,845 
(64%) 
322 
(11%) 
233 
(8%) 
358 
(12%) 
114 
(4%) 
UCSF Prostate 
Cancer (New 
Cases Seen in 
2006) 
807 
(100%) 
636 
(79%) 
45 
(6%) 
26 
(3%) 
56 
(7%) 
44 
(5%) 
UCSF new 
prostate cancer 
pts. enrolled on a 
clinical trial (2006) 
100 
(100%) 
85 
(85%) 
5 
(5%) 
5 
(5%) 
4 
(4%) 
1 
(1%) 
*Bay Area Population Estimate numbers are listed for the 5 Bay Area Counties of San Francisco, San
Mateo,  Marin, Contra Costa and Alameda.
3.4  Inclusion Criteria.  
Each patient must meet the following criteria to be enrolled in this study: 
3.4.1 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 
3.4.2 Be willing/able to adhere to the prohibitions and restrictions specified in this protocol 
3.4.3 Written Authorization for Use and Release of Health and Research Study Information has 
been obtained 
3.4.4 Male aged 18 years and above 
3.4.5 Able to swallow the study drug whole as a tablet 
3.4.6 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  
3.4.7 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 

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principal investigator and sponsor during the study and for 1 week after last study drug 
administration. 
3.4.8 Have a baseline serum potassium of ≥ 3.5 mEq/L 
3.4.9 Have aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin 
levels < 1.5 x ULN 
3.4.10 Have a serum albumin of ≥ 3.0 g/dL 
3.4.11 Total bilirubin ≤ 1.5 x ULN (In patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 
x ULN, with direct bilirubin ≤ 1.5 x ULN is acceptable) 
3.4.12 Have a platelet count of ≥ 100,000/μL 
3.4.13 Have an absolute neutrophil count of > 1500 cell/mm3 
3.4.14 Have a hemoglobin of ≥ 9.0 g/dL 
3.4.15 Have histologically confirmed adenocarcinoma of the prostate. 
3.4.16 No prior therapy with chemotherapy for metastatic prostate cancer. 
3.4.17 Have metastatic disease based on a positive bone scan or objective imaging on CT scan. 
3.4.18 Have ongoing gonadal androgen deprivation therapy with LHRH analogues or 
orchiectomy. Patients who have not had an orchiectomy must be maintained on effective 
LHRH analogue therapy for the duration of the trial. 
3.4.19 Testosterone < 50 ng/dL. 
3.4.20 Progressive disease after androgen deprivation, defined as either : 
-Objective radiographic progression as defined by RECIST or PCWG2 criteria
OR 
-PSA evidence for progressive prostate cancer which consists of a PSA level of at least 2
ng/ml which has risen on at least 2 successive occasions, at least 2 weeks apart (Fig 4 #2
& #3a). If the confirmatory PSA value is less (Fig 4 #3b) than the screening PSA (Fig 4 #2)
value, then an additional test for rising PSA (Fig 4 #4) will be required to document
progression
Figure 4: Eligibility based on PSA 

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3.4.21 Antiandrogen Withdrawal 
Patients who are receiving an antiandrogen as part of primary androgen ablation must 
demonstrate disease progression following discontinuation of antiandrogen.  
3.4.21.1 
Disease progression after antiandrogen withdrawal is defined as 2 consecutive 
rising PSA values, obtained at least 2 weeks apart, or documented osseous or soft 
tissue progression.  
3.4.21.2 
For patients receiving flutamide, at least one of the PSA values must be 
obtained 4 weeks or more after flutamide discontinuation. 
3.4.21.3 
For patients receiving bicalutamide or nilutamide, at least one of the PSA  
values must be obtained 6 weeks or more after antiandrogen discontinuation. 
3.4.21.4 
No antiandrogen withdrawal response is expected in patients in whom  
antiandrogen therapy did NOT result in a decline in PSA or in those patients in 
whom the response to antiandrogens was <3 months. Therefore, it is not 
necessary to wait for AAWD in pts without PSA decline on an anti-androgen or in 
those in whom a PSA response lasted <3 months. 
3.4.22 ECOG Performance Status 0-1 
3.4.23 Life expectancy of 12 weeks.  

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3.5 Exclusion Criteria. 
Patients who meet any of the following criteria will be excluded from the study: 
3.5.1 Active infection or other medical condition that would make prednisone/prednisolone 
(corticosteroid) use contraindicated 
3.5.2 Known brain metastasis 
3.5.3 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. 
3.5.4 Active or symptomatic viral hepatitis or chronic liver disease 
3.5.5 History of pituitary or adrenal dysfunction 
3.5.6 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 known cardiac ejection fraction 
measurement of <50 % at baseline. No echocardiogram or MUGA scan is required for 
study entry.  
3.5.7 Administration of an investigational therapeutic within 30 days of screening 
3.5.8 Have poorly controlled diabetes 
3.5.9 Have a history of gastrointestinal disorders (medical disorders or extensive surgery) that 
may interfere with the absorption of the study agents 
3.5.10 Have a pre-existing condition that warrants long-term corticosteroid use in excess of study 
dose 
3.5.11 Have known allergies, hypersensitivity, or intolerance to abiraterone acetate or prednisone 
or their excipients 
3.5.12 Any condition which, in the opinion of the investigator, would preclude participation in this 
trial. 
3.5.13 Pure small cell carcinoma of the prostate or any mixed histology cancer of the 
prostate (eg: neuroendocrine) which contains <50% adenocarcinoma. 
3.5.14 Therapy with other hormonal therapy, including any dose of megestrol acetate 
(Megace), finasteride (Proscar), dutasteride (Avodart) any herbal product known to 
decrease PSA levels (e.g., Saw Palmetto and PC-SPES), or any systemic corticosteroid 
within 4 weeks prior to first dose of study drug.   
3.5.15 Prior therapy with Abiraterone Acetate or other CYP17 inhibitor(s) including TAK-700 
or TOK-001, or second-generation agent(s) targeting the androgen receptor including 
MDV-3100, ARN-509 for metastatic prostate cancer.

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3.5.16 Prior therapy with ketoconazole for >2 weeks for prostate cancer. 
3.5.17 Therapy with supplements or complementary medicines/botanicals not known to decrease 
PSA must be discontinued prior to the first dose of study drug, except for any combination 
of the following which may be continued while on study treatment: 

Conventional multivitamin supplements

Selenium

Lycopene

Soy supplements
3.5.18 Prior radiation therapy completed < 4 weeks prior to enrollment 
3.5.19 Prior chemotherapy for castration resistant prostate cancer. Patients who have 
received chemotherapy for early stage prostate cancer (e.g. as part of a neoadjuvant or 
adjuvant trial) or for other malignancies are eligible provided that >1 year has passed 
since the administration of the last chemotherapy dose.  
3.5.20 Any “currently active” second malignancy, other than non-melanoma skin cancer. 
Patients are not considered to have a "currently active” malignancy, if they have 
completed therapy and are considered by their physician to be at least less than 30% risk 
of relapse over next year. 
3.5.21 Active psychiatric illnesses/social situations that would limit compliance with protocol 
requirements. 
3.5.22 Patients in whom urgent chemotherapy, in the opinion of the treating physician, is 
indicated should not be enrolled in this study. 
4.0 DRUG INFORMATION 
4.1 DOSAGE AND ADMINISTRATION 
Treatment will be administered on an outpatient basis and will consist of 28-day cycles. 
Initial therapy will consist of Abiraterone Acetate, 1000 mg per day, plus prednisone 5 mg po bid.  
Abiraterone Acetate will be taken once daily in the form of four 250 mg-tablets.  Abiraterone 
Acetate will be administered 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. Patients should be instructed to take Abiraterone 
Acetate at the same time each day. 
Participants will keep a drug diary to record each dose of study drug taken (see Appendix D). Any 
missed doses should be recorded on the dosing diary. Subjects will be required to bring the 
dosing diary to every visit unless instructed otherwise.  
Because short-term rises in PSA after the initiation of Abiraterone Acetate therapy may be 
followed by meaningful response, the PSA at 12 weeks will be the first value requiring action.  
Patients who do not experience any decline in PSA while on Abiraterone Acetate at the 12 week 

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evaluation time point will be withdrawn from the study, Abiraterone Acetate will be stopped, and 
prednisone tapered off.  Patients continuing Abiraterone Acetate/prednisone off-study OR those 
planning to receive subsequent chemotherapy do not need to taper prednisone.  Patients coming 
off study at this point will have off study labs, CTCs, and optional metastatic biopsy (see Section 
5.1.3). 
In patients in whom a decline in PSA of any magnitude is achieved by week 12, Abiraterone 
Acetate and prednisone therapy will continue until progressive disease (PD#1) defined is 
documented. Progressive disease is defined by either RECIST criteria (as defined in Appendix 
B) OR by PSAWG2 criteria (as defined in Appendix C) – requiring a 25% increase in PSA above
the nadir and an increase in the absolute-value PSA levels back to baseline or by 2ng/ml,
confirmed at least 2 weeks afterwards, or by PCWG2 bone scan criteria.  At time of progression
(referred to as PD #1), Androstenedione, DHEA and DHEAS and Abiraterone Acetate levels will
be measured and prednisone will be continued.  Abiraterone Acetate 1000 mg by mouth BID
(q12 hours) will be initiated after Abiraterone and hormone levels are measured.  ACTH, PSA,
and an electrolyte and liver function panel (“serum chemistries”) will be measured. They will be
measured again 2 weeks later and then again at the beginning of the next cycle with other
hormone and laboratory levels as specified in Table 3.
Patients receiving Abiraterone Acetate 1000 mg BID plus prednisone 5 mg po BID, who are 
tolerating therapy well, will continue on therapy for 12 weeks, which will be the first point at which 
criteria for progressive disease #2 (as defined by PCWG2 and/or RECIST criteria) may be 
determined. This includes patients who do not achieve any PSA decline in response to  
increased-dose therapy. Once PCWG2 criteria for progressive disease is met the patients will 
come off study. This will be considered PD#2.  
DURATION OF TREATMENT 
Patients will continue on therapy until any one of the following events occurs: 
o
No evidence of any PSA decline at evaluation #1, after 12 weeks of treatment
o
Progressive disease #2, determined after 12 weeks of increased-dose therapy.
o
Any unacceptable treatment-related toxicity
o
Patient‟s withdrawal of consent
o
Discretion of Principal Investigator
Adverse events and Dose Reductions 
Reported adverse events and toxicity are described in Section 5.7 
Dose reductions in response to toxicity are detailed in Section 5.7 
4.2 Prednisone 
Prednisone is an analogue of cortisol is believed to be the principal hormone secreted by the 
adrenal cortex. Naturally occurring glucocorticoids (prednisone and cortisone) have salt-retaining 
properties and are used as replacement therapy in adrenocortical deficiency states. They have 
potent anti-inflammatory effects and modify the body‟s immune response to adverse stimuli. 
Availability - Prednisone is commercially available in 5mg tablets. 
Administration - Prednisone is administered orally with food at 5mg every morning and 5mg at 
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Storage - Prednisone should be stored in well-closed containers at a temperature less than 
400C, preferable 15-300C. 
Toxicities - Prednisone may cause fluid and electrolyte disturbances, especially sodium 
retention and potassium loss; muscle weakness; peptic ulcer; impaired wound healing; thin 
fragile skin; petechiae and ecchymoses; psychic disturbances; manifestation of latent diabetes 
mellitus; hypertension; cataracts; weight gain; and nausea. 
Precautions - Patients who have been on prednisone for longer than 4 weeks should have the 
drug gradually tapered rather than abruptly stopped. If the patient is subjected to unusual 
physiologic stress, increased dosage before, during, and after the stressful situation is indicated. 
It is recommended that hydrocortisone (an analogue of prednisone) 100mg administered 
intravenously every 8 hours be utilized until the physiologic stress has ended, at which point the 
normal replacement dosage of prednisone (see above) is resumed. 
4.3 Abiraterone Acetate 
Abiraterone Acetate 250-mg tablets are oval, white to off-white and contain Abiraterone Acetate 
and compendial (USP/NF/EP) grade lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, colloidal silicon 
dioxide, and purified water, in descending order of concentration (the water is removed during 
tabletting).  
Availability – Abiraterone Acetate will be supplied by Janssen Services in 250mg tablets. 
Administration – Patients will be instructed to take 4 tablets (1000mg) orally (PO) once or twice 
daily (BID). 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. 
Storage –Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 
86°F) 
Toxicities - Abiraterone Acetate may cause fluid and electrolyte disturbances, edema, 
hypertension, liver function abnormalities, muscle discomfort, back pain, hot flushes, diarrhea, 
urinary tract infections, cough, arrythmia, urinary frequency, nocturia, dyspepsia, and upper 
respiratory tract infection. 
Precautions - Mineralocorticoid excess: Use Abiraterone Acetate with caution in patients with a 
history of cardiovascular disease. The safety of Abiraterone Acetate in patients with LVEF < 50% 
or NYHA Class III or IV heart failure is not established. Control hypertension and correct 
hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid 
retention is recommended at least monthly. Adrenocortical insufficiency: Monitor for symptoms 
and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated 
before, during and after stressful situations. (5.2)  Hepatotoxicity: Increases in liver enzymes 
have led to drug interruption, dose modification and/or discontinuation. Monitor liver function and 
modify, interrupt, or discontinue Abiraterone Acetate dosing as recommended. Food Effect: 
Abiraterone Acetate must be taken on an empty stomach. Exposure (area under the curve) of 
Abiraterone Acetate increases when Abiraterone Acetate is taken with meals.  
Drug Interactions – Based on in vitro data, Abiraterone Acetate is a substrate of CYP3A4. In a 
dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, 

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decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during 
Abiraterone Acetate treatment. If a strong CYP3A4 inducer must be co-administered, increase 
the Abiraterone Acetate dosing frequency.  In a dedicated drug interaction trial, co-administration 
of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the 
pharmacokinetics of abiraterone. 
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 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of 
abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., 
thioridazine).  If alternative treatments cannot be used, exercise caution and consider a 
dose reduction of the concomitant CYP2D6 substrate drug. 
In vitro, Abiraterone Acetate inhibits CYP2C8. There are no clinical data on the use of 
Abiraterone Acetate with drugs that are substrates of CYP2C8. However, patients should be 
monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with 
abiraterone acetate. 
Pregnancy - Abiraterone Acetate may cause fetal harm when administered to a pregnant 
woman. Men who are sexually active with a pregnant women must use a condom during and for 
one week after treatment with Abiraterone Acetate. If their sexual partner may become pregnant, 
a condom and another form of birth control must be used during and for one week after treatment 
with Abiraterone Acetate. Pregnant women or women who may be pregnant should not handle 
abiraterone acetate.  
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 STUDY PROCEDURES AND OBSERVATIONS 
5.1 Schedule of Procedures and Observations 
The study-specific assessments are detailed below and are outlined in Table 3, Schedule of 
Study Procedures and Assessments, Screening assessments must be performed within 28 days 
prior to the first dose of investigational product.  Any results falling outside of the reference 
ranges may be repeated at the discretion of the investigator.  All on-study visit procedures are 
allowed a window of ± 3 days unless otherwise noted. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the consent form will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.   

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All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements. 
5.1.1  SCREENING ASSESSMENTS 
Clinical:  
Required within 28 days before the first cycle: 

Signed informed consent

History and physical examination, including height, weight, and vital signs and review of
systems

ECOG performance status

Concomitant Medication review
Laboratory / Diagnostic: required within 28 days before the first cycle. 

CBC, platelet count, and automated differential

Serum chemistries: includes BUN, Creatinine, ALT, AST, glucose, alkaline phosphatase,
total bilirubin, electrolytes (K+, CL-, Na+, CO2, Mg, Ca+, Phos)

Prostate Specific Antigen (PSA)

LDH

Urinalysis

ECG

Endocrine analysis

Adrenal Androgen Levels - Testosterone, Dihydrotestosterone, Androstenedione, DHEAS,
DHEA

HPA Axis Hormones - FSH and LH

Correlative studies

Circulating tumor cells

Genotyping

Metastatic Biopsy – optional
Imaging/Diagnostic: Must be performed within 45 days before starting the first cycle: 

CT Abdomen/Pelvis or MRI Abdomen/Pelvis.

Bone Scan. Bone scan may be either a Technetium-99 bone scan or a sodium-fluoride PET
scan. All subsequent bone imaging should be done with the same type of scan used at study
entry.
5.1.2  TREATMENT PERIOD 
The following assessments will be performed monthly during the treatment period unless 
otherwise noted.   
Clinical Assessments 

Physical examination (including weight) and vital signs

ECOG Performance Status

Adverse Events

Concomitant Medication review
Laboratory Evaluation - Within 72 hours prior to visit the following blood tests will be performed: 

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
PSA

CBC, platelet count, and automated differential

Serum chemistries: include BUN, creatinine, ALT,AST, glucose, alkaline phosphatase, total
bilirubin, electrolytes (Na+, K+, Cl-, Na+, CO2, MG, CA+, Phos). These will be checked every
2 weeks during the first 3 cycles of treatment (ie cycle 1 day 1, cycle 1 day 15, cycle 2 day 1,
cycle 2 day 15, cycle 3 day 1, cycle 3 day 15) for a total of 6 evaluations, then at the
beginning of each cycle thereafter.

LDH

Abiraterone Acetate level – Patients should hold abiraterone on these days until the level is
drawn. For patients taking the elevated dose, the AM dose should be held on these days.
These levels should be drawn at the same time of day for each patient, ideally between 8AM
and noon at the following visits:
o
the 1st study visit after patient begins taking standard dose Abiraterone Acetate (1000
mg daily)
o
the time of disease progression #1
o
the 1st study visit after the initiation of elevated-dose therapy
o
disease progression #2

Endocrine analysis – evaluated every 2 cycles
o
Adrenal Androgen Levels - Testosterone, Dihydrotestosterone, Androstenedione,
DHEAS, DHEA
o
HPA Axis Hormone Levels - FSH, LH, and ACTH

ECG – evaluated every 3 cycles
Imaging/Diagnostics - evaluated at the completion of every 3 cycles 

CT Abdomen/Pelvis or MRI Abdomen/Pelvis

Bone Scan or NaF-PET
Patients with bone-only disease at baseline are unlikely to develop new soft tissue disease if 
responding by PSA to Abiraterone Acetate and do not need to have serial imaging of the 
abdomen/pelvis with CT or MRI until the time of disease progression #1 (PD#1). If soft-tissue 
disease is found then these patients will undergo q3cycle bone scan and CT or MRI of the 
abdomen and pelvis. If no soft-tissue disease is found at PD#1 then patients do not need to 
have another CT or MRI until PD#2. 
Patients with soft tissue-only disease at baseline are unlikely to develop new bony lesions if 
responding by PSA to Abiraterone Acetate and do not need to have serial imaging with bone 
scans until the time of disease progression #1 (PD#1). If bony disease is found then these 
patients will undergo q3cycle bone scan and CT or MRI of the abdomen and pelvis. If no bony 
disease is found at PD#1 then patients do not need to have another bone scan until PD#2. 
If new soft-tissue or bone disease is discovered on a radiologic exam performed for non-study 
reasons then patients should be evaluated with the appropriate (bone scan or CT or MRI of 
the abdomen and pelvis) q3cycle imaging of the lesion. Repeat imaging does not need to 
occur if the last scan was within 8 weeks; if this is the case the next scan should occur at the 
next regularly scheduled assessment (ie if a scan done to confirm PD#1 is obtained during 
cycle 6, the next scan should be at cycle 10) 
5.1.3 Study procedures at the time of progression (PD#1) 
A critical aim of this study is to determine the endocrinologic and pharmacokinetic state of 
patients at the time of clinical progression. Thus, it is required that hormone and Abiraterone 

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Acetate levels be obtained from patients at the time of progression but prior to the Abiraterone 
Acetate dose increase.   At the time of clinical progression, the following evaluations will be 
performed. 
Clinical Assessments 

Physical examination (including weight) and vital signs

ECOG Performance Status

Adverse Events

Concomitant Medication review

ECG
Laboratory Evaluation 

CBC, platelet count, and automated differential

Serum chemistries

Circulating tumor cells

The following must be obtained prior to Abiraterone Acetate dose increase:

PSA

Abiraterone Acetate level

Endocrine analysis
o
Adrenal Androgen Levels - Testosterone, Dihydrotestosterone, Androstenedione,
DHEAS, DHEA
o
HPA Axis Hormone Levels - FSH, LH, and ACTH
If progression occurs during a period between visits (e.g. due to imaging done to evaluate 
pain) every effort should be made to continue therapy until such time as the above named 
blood tests  can be obtained.  
Metastatic Biopsy – optional 
Imaging/Diagnostics – if performed within previous 8 weeks, will not need to be repeated. 

CT Abdomen/Pelvis or MRI Abdomen/Pelvis

Bone Scan or NaF-PET
5.1.4 Study procedures at the time of dose increase 
After starting dose-increased Abiraterone Acetate (1000 mg BID), patients will continue to be 
monitored monthly as described in section 5.1.2, Treatment Period, until the time of second 
disease progression according to PSAWG 2 criteria (see Appendix C).  The following additional 
laboratory evaluations will be performed  
2 weeks after dose-increased Abiraterone Acetate 
Clinical Assessments 
o
ECG
o
Blood pressure check
Laboratory Evaluation 
o
An Abiraterone Acetate level will be drawn
o
ACTH, PSA, and Electrolyte and liver function panels (serum chemistries) will be drawn

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4 weeks after dose-increased Abiraterone Acetate 
Clinical Assessments 
o
ECG
Laboratory Evaluation 
o
Adrenal Androgen Levels - Testosterone, Dihydrotestosterone, Androstenedione,
DHEAS, DHEA
o
HPA Axis Hormone Levels - FSH, LH, and ACTH
o
PSA, and Electrolyte and liver function panels (serum chemistries) will be drawn 4 weeks
after dose-increased Abiraterone Acetate (at the first monthly visit)
o
Note that adrenal androgen and HPA axis hormone levels should continue to be drawn
every 2 cycles (ie every “odd” cycle – C1, 3, 5, 7, 9….) regardless of the timing of PD#1. 
5.1.5 Study procedures at the time of second progression (PD#2) / End of Study Visit 
An end-of-study evaluation will be performed within 2 weeks of the last dose. This includes 
subjects who did not experience an initial decline in PSA to standard-dose Abiraterone Acetate. 
The end of study visit will include the following: 
Clinical Assessments 

Physical examination (including weight) and vital signs

ECOG Performance Status

Adverse Events

Concomitant Medication review

ECG
Laboratory Evaluation 

PSA

CBC, platelet count, and automated differential

Serum chemistries: include BUN, creatinine, ALT,AST, glucose, alkaline phosphatase, total
bilirubin, electrolytes (Na+, K+, Cl-, Na+, CO2, MG, CA+, Phos).

LDH

Abiraterone Acetate level

Endocrine analysis – evaluated every 2 cycles

Adrenal Androgen Levels - Testosterone, Dihydrotestosterone, Androstenedione, DHEAS,
DHEA

HPA Axis Hormone Levels – FSH and LH

Circulating tumor cells
Imaging/Diagnostics - if performed within previous 8 weeks, will not need to be repeated. 

CT Abdomen/Pelvis or MRI Abdomen/Pelvis

Bone Scan or NaF-PET
Metastatic Biopsy – optional  
5.2 Abiraterone Acetate Levels 

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Abiraterone Acetate levels to be drawn four (4) times during study, as described above and in Table 
3. Abiraterone Acetate levels to be drawn in separate serum chemistry test tube, then stored and
shipped to the UCSF Drug Studies unit for evaluation per drug study unit protocol.
5.3 Genotype Analysis 

Eighteen mls of whole blood in 2 plastic EDTA tubes and 1 serum tube will be collected from
patients during their first study visit and freshly frozen at -80 degrees centigrade in the UCSF
Cancer Center.

Batched germline DNA will be isolated from peripheral whole blood mononuclear cells by the
UCSF genomics core facility in standardized aliquots according to the UCSF DNA bank
protocol, with an estimated yield of ~1 microgram of DNA per sample.

DNA samples will be de-identified and transported on ice to the Kroetz laboratory at UCSF
Mission Bay for SNP analysis.

Samples will be genotyped for the rs743572 SNP as well as other SNPs in the CYP17A1
gene in the Kroetz laboratory at UCSF using a commercially available Applied Biosystems
(ABI) SNPlex™ Genotyping System according the manufacturer‟s instructions.

Samples will be used for this study only.  Any remaining germline blood samples will be
destroyed at the end of the study.
5.4 Circulating tumor cells 
Blood for circulating tumor cell studies will be drawn 3 times during subject‟s participation in this 
study: 
o
prior to the first dose of Abiraterone Acetate
o
at PD#1 (prior to Abiraterone Acetate dose increase for patients who experienced a
decline in PSA on standard dose Abiraterone Acetate. CTCs should also be collected
at the off study visit for patients who do not experience any PSA decline)
o
at PD#2. Cells may be taken before discontinuation of Abiraterone Acetate (preferred)
or after the discontinuation of Abiraterone Acetate.

40ml of peripheral blood will be drawn in sodium or lithium heparin coated tubes, deidentified
to protect patient privacy, and delivered freshly to the Paris Lab at UCSF. This can be done at
any time after PD#1 has been documented and prior to the first dose of Abiraterone Acetate
1000mg BID.

A additional 10ml of peripheral blood will be drawn (total 50ml including CTCs to be sent to
Paris lab) will take place simulatenously into blood collection tubes containing preservative
provided by Epic Sciences and will be shipped directly to the Epic Sciences processing
facility. These should be placed into ambient blood shipping containers provided and shipped
on the same day of the blood draw with the goal of arrival within 48 hours of blood draw.

An additional optional 7.5ml of peripheral blood will be collected for CTC cell counting
(enumeration only) using the Veridex Cell Search® System. This will be shipped to Veridex
and analyzed per a standardized protocol. Samples will be destroyed after Veridex CTC
enumeration.

Blood drawn for circulating tumor cells will be de-identified, transported on ice to, and any
residual cells will be banked at the UCSF HDFCCC Tissue Core for up to 10 years for future
genetic studies. These studies could potentially include immunohistochemical analysis of
androgen receptor levels, CYP17A1 levels, or levels of other enzymes involved in androgen
biosynthesis. Other potential studies include SNP studies to correlate single base mutations
in other androgen synthesis genes with clinical outcomes, or potentially gene expression
array analyses. Pathways to be explored could include the androgen synthesis pathway as
well as the PTEN/PI3 Kinase/mTOR pathways. See section 7.5.4 for CTC isolation rationale
and methods

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5.5 Metastatic Biopsies 
Optional metastatic biopsies will be collected during study.  While optional, these should be strongly 
encouraged for all study participants.  Tumor biopsies will be conducted at the following times: 

prior to the first dose of Abiraterone Acetate AND

at PD#1 prior to Abiraterone Acetate dose increase AND

at PD# 2 after Abiraterone Acetate dose increase
Biopsy at UCSF will take place in the Department of Radiology using a CT guided or ultrasound 
guided approach.  One biopsy will be processed for decalcification, fixation, and paraffin embedding 
for immunohistochemical analysis and identification of tumor sample.  The other biopsies will be 
frozen immediately at the time of biopsy for microarray analysis which will take place in the Paris and 
Febbo labs at UCSF.  Any leftover biopsy samples will be banked at the UCSF HDFCCC Tissue 
Core for up to 10 years for potential future genetic studies as outlined above.

Table 3: Treatment Calendar 
All on-study visit procedures are allowed a window of ± 3 days unless otherwise noted. 
Screening 
Day 1 of 
every cycle a
Day 15 of 
cycles 1-3 
Every 2 
cycles 
(C1,3,5,7…) 
Every 3 
cycles 
(C1,4,7,10…) 
Time of initial 
clinical 
progression 
(PD#1) b 
2 weeks 
after dose-
increase 
4 weeks 
after dose-
increase 
Second 
progression 
(PD#2) and end of 
study c
  Procedures 
Informed Consent d 
X 
Medical History, including 
demographics
X 
Physical exam, including 
height (only at screening) and 
weight 
X 
X 
X 
X r
X 
X 
Vital signs e
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
ECG 
X 
X 
X f
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
Concurrent Anti Cancer 
Therapies g
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Laboratory Assessmentsa
CBC, serum chemistries h 
X 
X i
X 
X j
X 
X i
X 
Abiraterone Acetate Level k
X 
X 
X 
X 
 PSA 
X 
X i
X j
X 
X i
X 
Adrenal Androgen Levels l 
X 
X 
X 
X s
X 
X 
HPA Axis hormone m
X 
X 
X j
X 
X 
LDH 
X 
X i
X 
X i
X 
Urinalysis (dipstick) 
X 
Tumor Assessments n
Bone scan 
X o
X p
X p
X p
CT or MRI of the 
abdomen/pelvis
X o
X p
X p
X p
Correlative Studies q
Circulating tumor cells 
X 
X 
X 
Metastatic Biopsy 
X 
X 
X 
Genotyping 
X 

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a. Unless otherwise noted, may be performed up to 72 hours prior to visit.
b. Required that drug and hormone levels be obtained from patients at the time of progression but prior to dose increase of Abiraterone Acetate. If progression
occurs during a period between visits (e.g. due to imaging done to evaluate pain) every effort should be made to continue therapy until such time as the
following tests (adrenal androgens, testosterone, HPA axis hormones, Abiraterone Acetate levels, circulating tumor cells, metastatic biopsy ) can be
obtained.
c. End of study visit – within 2 weeks of the last Abiraterone Acetate dose.
d. Written informed consent must be obtained before any screening assessments are performed (it can be no more than 28 days prior to starting the trial).
e. Includes blood pressure, pulse, respiratory rate, and body temperature.
f. ECG should be performed at the time of PD#1 and again 2 and 4 weeks later after dose-increase.
g. Other than LHRH agonists that are required to maintain castrate levels of testosterone, anti-cancer therapies are excluded during this study. These include
chemotherapy, radiotherapy, immunotherapy, ketoconazole, diethylstilbesterol, PC-SPES, and other experimental anticancer medications, such as herbal
preparations.  Bisphosphonates and bone anti-resorptive therapies may be started at any point during the course of treatment. See sections 3.5 and 5.6.
h. CBC includes platelets and differential. Serum chemistry includes BUN, creatinine, ALT, AST, glucose, alkaline phosphatase, total bilirubin, electrolytes (K+,
Cl-, Na+,CO2, Mg, Ca+, Phos). These will be checked every 2 weeks for the first 3 cycles for a total of 6 evaluations, and then once each cycle thereafter.
See section 5.1.2. These will be also be checked 2 weeks after the Abiraterone Acetate dose increase as described in section 5.1.4
i. No need to repeat if performed within the previous 7 days.
j. PSA, ACTH, and serum electrolytes and liver function to be drawn 2 weeks after initiating increased dose Abiraterone Acetate, then again 2 weeks later at
the beginning of the next cycle.
k. Abiraterone Acetate levels performed on first scheduled office visit (Cycle 2 day 1) after patient begins taking Abiraterone Acetate, then again at time of initial
clinical progression, then again on first visit after patient begins taking higher dose Abiraterone Acetate, then at time of second clinical progression. Total = 4
Abiraterone Acetate levels. Patients should hold Abiraterone Acetate on these days until after the blood draw. Level should be obtained at similar times for
each patient, ideally between 8AM and noon.
l. Within 14 days up to and including on cycle 1 day 1 prior to the first dose of therapy, and then evaluated every 2 cycles - Testosterone, Dihydrotestosterone,
Androstenedione, DHEAS, DHEA
m. Within 14 days and then evaluated every 2 cycles - FSH and LH, ACTH.
n. Can be either technetium-99 or sodium-fluoride PET. Choice of scan must be maintained for all subsequent evaluations.  If no soft-tissue disease present at
baseline then CT/MRI only needed at PD#1. If no soft-tissue disease present at PD#1 then next CT/MRI is at PD#2. Similarly if no bony disease present at
baseline then bone imaging only needed at PD#1. If no bony disease present at PD#1 then next bone imaging is at PD#2.
o. May be performed within 45 days of starting therapy
p. Within +/- 8 days.  Does not need to be repeated if performed within the previous 8 weeks.  To be completed at the end of every 3 cycles.
q. May occur any time during the screening period up to and including on cycle 1 day 1 prior to the first dose of therapy. Subsequent evaluations may occur
within +/- 14 days provided no change in therapy (ie: commencement of therapy, dose escalation, dose discontinuation) has occurred yet.
r. Blood pressure check only
s. ACTH only

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5.6 Concomitant medications 
Concurrent Anti Cancer Therapies - Other than LHRH agonists that are required to maintain castrate 
levels of testosterone, anti-cancer therapies are excluded during this study. These include 
chemotherapy, radiotherapy, immunotherapy, ketoconazole, diethylstilbestrol, PC-SPES, and other 
experimental anticancer medications, such as herbal preparations. See Appendix E for 
comprehensive listing of medications that should be avoided. Bisphosphonates and bone anti-
resorptive therapies may be started at any point during the course of treatment. Calcium and Vitamin 
D are allowed at any point on study. 
5.7 DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
5.7.1 Adverse Event (AE) Description and Grade: The descriptions and grading scales found in 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of 
the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site. (See Appendix A)  
5.7.2 Dose Modification Guidelines for Strong CYP3A4 Inducers 
Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentine, phenobarbital) during ZYTIGA treatment. Although there are no 
clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers, 
because of the potential for an interaction, if a strong CYP3A4 inducer must be co-
administered, increase the ZYTIGA dosing frequency to twice a day only during the co-
administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). Reduce the 
dose back to the previous dose and frequency, if the concomitant strong CYP3A4 inducer 
is discontinued. See appendix E 
5.7.3 Management of Non-Mineralocorticoid Based Side Effects: 
Management of specific toxicities attributed to Abiraterone Acetate and prednisone are 
discussed in Section 4.2, 4.3.  
If Grade 1-2 toxicities, and for grade 3 toxicities that are not considered clinically relevant in 
the opinion of the treating investigator give supportive care per institutional guidelines. No 
study treatment dose reduction. 
For Grade 3-4 toxicity related to study treatment that is considered clinically relevant in the 
opinion of the treating investigator, hold study treatment and adjust or add medications to 
mitigate the toxicity. When resolved to Grade 1 or less resume as follows:  

If subject was taking 1000 mg at the time of a Grade 3/4 toxicity then study drug may be
restarted at full dose.

If subject was taking 1000 mg BID at the time of a Grade 3/4 toxicity, when study drug
is resumed it will be at 750 mg BID (a 25% dose reduction). There will be no dose
reescalation for these patients.
If the same Grade 3-4 toxicity recurs that is considered clinically relevant in the opinion of 
the treating investigator and is due to study treatment, hold study treatment, and adjust or 

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add medications to mitigate the toxicity. When resolved to Grade 1 or less proceed as 
follows:  

If subject was taking 1000 mg at the time of a recurrent Grade 3/4 toxicity that is
considered clinically relevant then permanently discontinue study treatment. No dose
reduction below 1000mg will be permitted as patients intolerant of a 1000 mg dose will
be intolerant of a 1000 mg BID dose as well.

If subject was taking 750 mg BID at the time of recurrent Grade 3/4 toxicity that is
considered clinically relevant, then permanently discontinue study treatment. No dose
reduction below 750 mg BID will be permitted for these patients.
If Abiraterone Acetate is held for toxicity, missed days of therapy are not made up.  When 
Abiraterone Acetate is held temporarily prednisone should be continued. 
When Abiraterone Acetate is permanently discontinued prednisone can be continued or 
tapered off at the treating physician‟s discretion. 
Patients who require >4 weeks to recover from grade 3/4 toxicity (initial or recurrent) will not 
be allowed to restart study drug at any dose. 
5.7.4 
Hypokalemia 
At the initial observation of Grade 1 or 2 hypokalemia (serum potassium <3.5 mM but >3.0 
mM), oral potassium supplement will be initiated.  Abiraterone Acetate may be continued at 
current dose. The dose of potassium supplement for patients with Grade 1 or 2 
hypokalemia must be carefully titrated to maintain serum potassium at >3.5 mM but <5.0 
mM. Any patient with low potassium while on study or a history of hypokalemia from a pre-
existing or concurrent medical condition will undergo weekly or more  frequent laboratory 
electrolyte evaluation. The investigator should consider maintaining the patient‟s potassium 
level at ≥ 4.0 mM in these patients. 
If any patient experiences Grade 3 hypokalemia (serum potassium levels <3.0 mM –but 
>2.5 mM) or Grade 4 hypokalemia (life-threatening hypokalemia with potassium levels <2.5
mM) study treatment will be withheld, and the patient hospitalized for intravenous
potassium replacement and cardiac monitoring. Reinitiating study treatment after
normalization of potassium levels must be discussed with and approved by the Sponsor-
Investigator. Potassium levels should be monitored weekly or more frequently if clinically
indicated until the end of treatment.
.
Hypokalemia 
Grade 1 (< 3.5 mM – 3.0 mM) 
Maintain dose level.  Initiate oral potassium supplement. The dose 
of potassium must be carefully titrated to maintain serum K+ at > 3.5 
mM but < 5.0 mM.  Conduct weekly (or more) laboratory electrolyte 
evaluations.  Consider maintaining K+ at > 4.0 mM. 

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Grade 3 (< 3.0 mM – 2.5 mM) 
Withhold Abiraterone and then: 

Initiate IV K+ and cardiac monitoring

If resolved, contact Study PI prior to re-initiation of study
treatment.
Continue to monitor K+ every week or more frequently if clinically 
indicated until the end of treatment. 
Grade 4 (< 2.5 mM) 
Withhold Abiraterone and then: 

Initiate IV K+ and cardiac monitoring

If resolved, contact Study PI prior to re-initiation of study
treatment.
Continue to monitor K+ every week or more frequently if clinically 
indicated until the end of treatment. 
5.7.5 Hypertension 
Grade 1-2 or Grade 3 not considered clinically relevant : Management per treating 
physician. No study treatment dose reduction. 
Grade 3-4: If clinically relevant hold study treatment. Adjust or add medications to mitigate 
the hypertension and/or consider the specific mineralocorticoid receptor blocker, 
Eplerenone (Inspra). When hypertension resolves to Grade 1 or less, resume study 
treatment at full dose. Continue to monitor blood pressure at least monthly. 
If Grade 3-4 toxicity recurs and is considered clinically relevant in the opinion of the treating 
investigator, hold study treatment, and adjust or add medications to mitigate the toxicity. 
When resolved to Grade 1 or less, proceed as follows resume study treatment as follows: 
o
If subject was taking 1000 mg at the time then permanently discontinue study
treatment. No dose reduction below 1000mg will be permitted as patients intolerant of a
1000 mg dose will be intolerant of a 1000 mg BID dose as well.
o
If subject was taking 1000 mg BID at the time then when study drug is resumed it will
be at 750 mg BID (a 25% dose reduction). There will be no dose reescalation for these
patients.
If Grade 3-4 hypertension recurs and is considered clinically relevant in the opinion of the 
treating investigator in patients taking 750 mg BID then permanently discontinue study 
treatment, and adjust or add medications to mitigate the toxicity.  
5.7.6 Pedal edema 
Supportive management per Investigator. No study treatment dose reduction. Monitor for 
symptoms of fluid retention at least monthly. 
5.7.7 Anasarca or pulmonary edema requiring supplemental oxygen 
Hold study treatment. Adjust or add medications to mitigate the edema and/or consider the 
specific mineralocorticoid receptor blocker, Eplerenone (Inspra). When edema resolves to 
Grade 1 or less, resume study treatment at full dose. Potassium levels should be followed 
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If Grade 3-4 toxicity recurs, hold study treatment, and adjust or add medications to mitigate 
the toxicity. When resolved to Grade 1 or less, resume study treatment with a dose 
reduction as specified above. Potassium levels should be followed closely.  
If toxicity recurs despite optimal medical management and a dose reduction, discontinue 
study treatment. 
5.7.8 Management of Abnormal Liver Function Tests 
If Grade 1 increases in AST, ALT or bilirubin occur (e.g. increase in AST or ALT from ULN 
to 2.5X ULN; increase in total bilirubin from ULN to 1.5X ULN): The frequency of liver 
function test monitoring should be increased, if the Investigator judges that the laboratory 
abnormalities are potentially related to study medication. No study treatment dose 
reduction is required. 
If Grade 2 increases in AST, ALT or bilirubin occur (e.g. increase in AST or ALT to >2.5-5X 
ULN; increase in total bilirubin from >1.5-3X ULN): The frequency of liver function test 
monitoring should be increased to at least once a week, if the Investigator judges that the 
laboratory abnormalities are potentially related to study medication. No study treatment 
dose reduction is required. 
If Grade 3 or higher increases in AST, ALT, or bilirubin occur: 
For patients who develop hepatotoxicity during treatment with Abiraterone acetate with the 
following parameters: ALT and/or AST greater than 5X ULN or total bilirubin greater than 
3X ULN, interrupt treatment with Abiraterone acetate. All other medicines that are 
potentially hepatotoxic should be interrupted as well. The Sponsor Investigator should be 
contacted and frequent laboratory evaluations (at least once weekly) should be conducted 
until the liver function tests return to baseline value or Grade 1. Liver enzyme 
measurements should be made immediately, regardless of when the next study visit or 
monitoring interval is scheduled. 
For patients who resume treatment, monitor serum transaminases and bilirubin at a 
minimum of every two weeks for three cycles and every cycle thereafter. 
If study treatment resumption is considered for subjects who have experienced Grade 3 
increases in AST, ALT, or bilirubin, and the Sponsor Investigator agrees, patients will be treated 
as follows:  

If subject was taking 1000 mg at the time then permanently discontinue study
treatment. No dose reduction below 1000mg will be permitted as patients intolerant of a
1000 mg dose will be intolerant of a 1000 mg BID dose as well.

If subject was taking 1000 mg BID at the time then when study drug is resumed it will
be at 750 mg BID (a 25% dose reduction). There will be no dose reescalation for these
patients.
If Grade 3 increases in AST, ALT, or bilirubin recurs in patients taking 750 mg BID then 
permanently discontinue study treatment and all other concomitant medications that are 
potentially hepatotoxic. Frequent laboratory evaluations (at least once weekly) should be 

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conducted until the liver function tests return to baseline value or Grade 1. Liver enzyme 
measurements should be made immediately, regardless of when the next study visit or 
monitoring interval is scheduled. 
If Grade 4 increases in AST, ALT, or bilirubin occur: 
The safety of Abiraterone Acetate re-treatment of patients who develop Grade 4 increases 
in AST or ALT (greater than or equal to 20X ULN) or bilirubin (greater than or equal to 10X 
ULN) is unknown. Patients must therefore discontinue study treatment and any potentially 
hepatotoxic medications immediately and will not be re-challenged with Abiraterone 
Acetate. The Sponsor Investigator should be contacted and frequent laboratory evaluations 
(at least once weekly) should be conducted until the liver function tests return to baseline 
value or Grade 1. 
5.7.9 Management of Symptoms Related to 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. Patients should be monitored for symptoms and 
signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone 
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. Increased dosage of corticosteroids may be indicated 
before, during and after stressful situations. A requirement of >10mg of prednisone (or 
corticosteroid equivalent) per day to treat adrenal insufficiency lasting longer than 2 weeks 
will result in discontinuation of study treatment. 
5.7.10 Management of Vasomotor Symptoms Related to Castration 
Treatment with androgens, estrogens and progestin to control hot flushes is not allowed. 
Selective serotonin re-uptake inhibitors (SSRIs) are permitted for the management of hot 
flashes 
5.8 Early stopping rule for safety 
If clinically relevant Grade 3/4 events attributable to study therapy occur in >1 of the first 6 
patients to take the 1000 mg BID dose, accrual will be stopped based on the observed 
frequency of toxicity and the Abiraterone Acetate dose to be administered will be reevaluated. 
If accrual continues after 6 patients then continuous monitoring will take place to ensure that 
Grade 3/4 events attributable to study therapy occur with a frequency of <20%. If at any time 
Gr3-4 events attributable to study therapy are observed at >20% frequency at the 2,000mg 
dose among all treated patients, then accrual will be stopped and the dose of Abiraterone 
Acetate reevaluated. See section 14 for data safety monitoring and adverse event reporting. 
5.9 ANCILLARY TREATMENT/SUPPORTIVE CARE GUIDELINES 
Concurrent supportive care is not restricted, including the use of narcotics for pain control and 
antiemetics for control of nausea, with the exception of the use of corticosteroids to treat 
nausea or acute adrenal insufficiency. Concurrent use of systemic corticosteroids for other 
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No investigational or commercial agents or therapies other than those included in protocol 
treatment may be administered with the intent to treat the patient‟s malignancy 
Concurrent chemotherapy, immunotherapy and radiation therapy are not permitted while on 
study. 
A requirement for radiation therapy will be considered as progression of disease even if PSA is 
not rising, and patients will be removed from study treatment. 
6 
CORRELATIVE STUDIES 
6.1 Pharmacogenomics 
All patients entering on study will have peripheral blood drawn for genotyping. Analysis of the 
association between genotype defined as homozygous wild type (A1A1), heterozygous (A1A2) 
and homozygous minor (A2A2) and PSA decline with standard-dose and with elevated-dose 
therapy will be considered exploratory. 
6.2 Adrenal androgen levels 
Adrenal androgen levels (Androstenedione, DHEAS, DHEA and Testosterone) will be collected 
at baseline, cycle 2 day 1 and every 2 cycles thereafter, as well as at the time of PD#1 (while 
patient is still on therapy with Abiraterone Acetate). Analysis of these levels in this patient 
population is considered exploratory. 
6.3 
Abiraterone Acetate Pharmacokinetics 
Abiraterone Acetate levels will be measured at the following four (4) times: at first visit after 
beginning low dose therapy (cycle 2 day 1), at the time of initial clinical progression, at first 
office visit after beginning dose increased therapy, and at the time of second clinical 
progression. The relationship between these values with the decline in PSA and disease 
progression will be evaluated.  
6.4 
Circulating Tumor Cells and Metastatic Biopsies 
All patients entering on study will have peripheral blood drawn for circulating tumor cell studies 
3 times during study.  Blood samples will be delivered freshly to the Paris Lab at UCSF or 
shipped directly to Veridex or Epic Biosciences. Biopsy will take place in the Department of 
Radiology at UCSF using a CT guided or ultrasound guided approach.  One biopsy will be 
processed for decalcification, fixation, and paraffin embedding for immunohistochemical 
analysis and identification of tumor sample.  The other biopsies will be frozen immediately at 
the time of biopsy for microarray analyses.  Microarray analyses will take place in the Paris and 
Febbo labs at UCSF. A sample of CTCs isolated in the Paris lab may be sent to Xcell 
Biosciences for culture for the purposes of CTC expansion for biologic characteriztion and 
genomic analysis. All cultured CTCs and biomaterials will be returned to UCSF, Leftover biopsy 
tissue will be banked at the UCSF Helen Diller Family Comprehensive Cancer Center Tissue 
Core for future genetics research.  Refer to section 7.5.3 and 7.5.4 for descriptions of the 
microarray analyses.   
The change in methylation status of specific promoter and intragenic CpG sites in CYP17A1 
and in a predefined set of 20 genes involved in androgen synthesis from prior to the first dose 
of Abiraterone Acetate 1000mg daily to the time of post-treatment disease progression (PD#1) 
will be explored in parallel using paired pre and post-treatment biopsy samples and in CTCs. 

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This analysis will take place in the Paris and Febbo labs at UCSF.CTCs isolated using Veridex 
CellSearch and Epic Biosciences will be assayed in an exploratory fashion for enumeration 
purposes, to provide a control for the Vitatex analyses, and to explore the relationship of 
disease progresson with the presence of nuclear and cytoplasmic AR, presence of PTEN 
deletion, and expression of mesenchymal markers.  
7 
STATISTICAL CONSIDERATIONS 
7.1 
Study Design 
This is a single arm, non-randomized, open–label multicenter phase II study of standard-dose 
Abiraterone Acetate (1000 mg/d) followed by elevated-dose Abiraterone Acetate (1000 
mg/BID) at the time of disease progression in patients with chemotherapy naïve, castration-
resistant metastatic prostate cancer.  
7.2 
Sample Size  
The hypothesis that patients who are refractory to standard dose Abiraterone Acetate will 
respond to dose increased Abiraterone Acetate will be tested. Using Simon‟s 2 stage minimax 
design for accrual, a test of a 20% (null) vs. 40% (alternative) proportion of patients achieving a 
≥ 30% PSA decline from baseline just prior to starting elevated-dose abiraterone after 12 
weeks of treatment requires a total of 33 patients. This test assumes a directional level of 
significance of 0.05 and power of 0.80. Based on the finding that approximately 85% of patients 
will achieve some PSA decline to standard-dose abiraterone in this population in Phase II and 
Phase III studies, 41 patients will need to be accrued in order to have 33 patients evaluable for 
the primary endpoint. If at least 5 out of the first 18 patients taking elevated-dose abiraterone 
achieve a ≥ 30% PSA decline, accrual will continue to the second stage and additional patients 
will be entered in order to enroll a total of 33 patients at the 1000mg BID level.  It is not 
necessary to stop accrual until stage 1 has been completed as these patients are Abiraterone 
Acetate naïve and are expected to respond to this therapy for a number of months prior to 
progression.  If less than 5 out of the initial 18 patients achieve a ≥30% PSA decline then 
accrual will be stopped. If at least 11 of the total 33 patients at the 1000mg BID dose on study 
achieve a ≥ 30% PSA decline, then the null hypothesis will be rejected.  The probability of 
stopping accrual at the first stage is 0.72 if the null hypothesis is true.   
7.3 
Primary Objective 
The primary objective of this study is to determine the efficacy of increased-dose Abiraterone 
Acetate for patients who experienced disease progression following standard-dose abiraterone 
acetate therapy. The primary study outcome measure is the proportion of patients who have 
had a PSA decline after 12 weeks of therapy with standard-dose Abiraterone Acetate, then had 
disease progression (Appendix C) and then achieved a ≥30% PSA decline after 12 weeks from 
the start of elevated-dose therapy. The proportion achieving a ≥30% PSA decline among those 
treated with elevated dose therapy among all patients entered on study along with 95% 
confidence intervals will be calculated to summarize the treatment effect. In addition to 
observing a ≥30% PSA decline, the proportion of patients treated with elevated-dose therapy 
achieving any PSA decline, maximum decline in PSA, and duration of initial and second 
response will be determined. The analysis of the primary objective will follow the decision rules 
for accrual to test the primary study objective.  
7.4 
Secondary Objectives 
7.4.1 Methods for analysis 

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The frequency of any toxicity with increased-dose Abiraterone Acetate by maximum observed 
grade will be tabulated for the study cohort. The Kaplan-Meier product limit method will be used 
to estimate the probability of PSA progression and PFS. Durations will be measured from the 
start of increased dose Abiraterone Acetate until PSA failure and progression or death due to 
any cause, respectively, as defined in Appendix C.  Point estimates from these analyses with 
95% confidence intervals will be presented to summarize the results.   
7.4.2 Pharmacokinetics 
Abiraterone Acetate levels will be measured at the following four (4) times: at first visit after 
beginning low dose therapy, at the time of initial clinical progression, at the first office visit after 
beginning dose increased therapy, and at the time of second clinical progression. For standard 
and increased dose Abiraterone Acetate the difference in means in baseline Abiraterone 
Acetate levels will be compared using a paired t test or to compare the distributions the 
nonparametric Wilcoxon matched pairs test will be performed for patients achieving any decline 
in PSA after 12 weeks of therapy with standard-dose abiraterone and are then treated with 
increased-dose Abiraterone Acetate. Similar methods for analysis will be used to investigate 
the change from baseline in Abiraterone Acetate levels at the time of PSA progression and 
overall disease progression.  Additional exploratory analyses including correlations between 
the change in Abiraterone Acetate levels and change in PSA at progression will also be 
performed. 
7.4.3 Hormone Levels 
Testosterone, DHEA, DHEA-S and androstenedione will be measured prior to the start of initial 
Abiraterone Acetate 1000mg mg daily and then every 2 cycles during standard and elevated-
dose study therapy. Measurements will be obtained at an earlier time point if the patient comes 
off study for disease progression before week 12. Pearson‟s correlation coefficients will be 
calculated to summarize the relationships among the 4 hormones at baseline and for the 
change from baseline at 12 weeks as well as between the baseline value and change at 12 
weeks for each hormone.   
The distribution of the baseline testosterone, DHEA, DHEA-S and androstenedione levels and 
the change in hormone level at 12 weeks will be compared between patients experiencing a 
PSA decline >30% and patients without such a PSA decline using a two group t statistic. 
Similarly, exploratory analysis using the t statistic will compare baseline and change from 
baseline at 12 weeks in hormone levels between each of the individual genotypes (A1A1, 
A1A2, A2A2) on the CYP 17 gene being evaluated versus the other two genotypes pooled 
together. Cox‟s proportional hazards model will be applied to explore the effect of the baseline 
level for each hormone on time to initial and second progression, as defined by PSAWG-2 
criteria. The relationship will be summarized by the hazard ratios with 95% confidence 
intervals. 
7.5 
Exploratory Objectives 
7.5.1 Genotype analysis 
The association of the presence of variant genotypes of CYP17A1 and a PSA decline  >30% to 
standard dose therapy will be determined as a secondary outcome measure of this analysis.  
PSA decline of >30% to elevated-dose therapy will also be explored here. It is estimated that 
approximately 40% of patients will respond to increased-dose Abiraterone Acetate therapy 
(based on the alternative hypothesis defined in this clinical trial) and there are three potential 
genotypes for CYP17 (A1A1, A1A2, A2A2). Additionally, the duration of initial response to 
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The proportion of patients for each of the 3 genotypes of CYP 17 achieving a PSA decline 
>30% to initial and to dose escalated Abiraterone Acetate therapy will be measured in this
analysis. For each patient the genetic profile will be defined according to the combinations of
reference type and variant genotypes. Proportions will summarize the distribution of the
individual 3 genotypes. Estimates of prevalence of genotypes in a prostate cancer population,
as in the general population, are shown below.
a) Common homozygote (Reference) - A1A1 (estimate 43%)
b) Variant homozygote  - A2A2 (estimate 14%)
c) Heterozygote-  A1A2 (estimate 43%)
To evaluate the association between declines in PSA (<30% vs >30%) and the genotypes, the 
association between each of the 3 individual genotypes vs. the others combined (e.g. presence 
of A1 allele vs none: A2A2 vs. A1A1+ A1A2) and PSA decline to Abiraterone Acetate therapy 
will each be tested using Fisher‟s exact test with a conservative level of significance of 0.05/3 = 
0.0167 using the Bonferroni correction for 3 comparisons. If there is no difference in achieving 
a PSA decline of at least 30% in a genotype subset, then a similar percent of the patients with 
an individual genotype and of the remaining pooled patients would be expected to respond to 
therapy. 
Exploratory multivariate models, logistic regression for PSA decline coded as a binary variable 
and Cox‟s proportional hazards model for time to progression, will be developed to analyze the 
combined effects of baseline hormone levels, change in hormone levels after 12 weeks of 
Abiraterone Acetate 1000mg daily and the presence of a genetic variant in the 3 genotypes on 
the CYP 17 gene. Each hormone will be evaluated separately due to the total planned sample 
size of 33. It is recognized that the sample size is small which will limit the number of variables 
that can be included in a model. The convention is to include 1 variable for every 10 evaluable 
patients. This will allow for evaluating up to 3 predictors in each model (baseline hormone level, 
change in hormone level at week 12 and 1 genotype).  A forward stepwise approach will be 
used (probability to enter set at 0.05 and the probability to remove set at 0.10) and univariate 
results will determine which variables will be included as potential independent predictors of 
outcome. Additional terms indicating an interaction between variables will be analyzed based 
upon the results. Because these are exploratory analyses the results will be used to develop 
future research. Cross-validation methods will be incorporated applied into to the multivariate 
analysis to control evaluate for overfitting of the model for overfitting.  
7.5.2 AR Expression Signature 
AR expression signatures will be derived in this study to determine whether the AR is 
transcriptionally active at the outset of therapy and at the time of treatment resistance. To 
determine the AR activation state at each time point, the level of expression of a defined set of 
300 AR-induced gene transcripts which have previously been shown to reliably predict AR 
activation24 will be examined in metastatic biopsies of men with ABI-naïve CRPC both prior to 
Abiraterone Acetate therapy and then again at the time of disease progression on Abiraterone 
Acetate 1000mg daily. This 300 gene AR transcriptional signature was derived by examining 
the set of genes with the strongest levels of differential expression between an androgen-
sensitive prostate cancer cell line prior to and following exposure to ligand, correcting for false 
discovery, and then subsequently validated on human prostate samples with known levels of 
androgen. To perform this analysis frozen biopsies will be processed for microarray analysis in 
the Febbo lab using laser capture microdissection and RNA amplification using adaptations of 
methods previously published. Briefly, prostate cancer cells will be microdissected from frozen 

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sections using an Arcturus Veritas Microdissection system and RNA isolated per a 
standardized protocol using the Absolutely RNA Nanoprep Kit (Stratagene, Agilent, Santa 
Clara, CA). RNA will be quantified, assessed for quality, amplified, labeled, hybridized to U133 
Plus 2.0 arrays for analysis (Affymetrix, Santa Clara, CA) and then analyzed using Affymetrix 
software. Standardized metrics will be used to assess RNA quality and only samples meeting 
quality standards will be used. Tumors will be assigned a probability of AR activity ranging from 
0 (absent) to 1 (present). Tumors will then be assigned an outcome variable of AR-active or 
AR-inactive using a conservative cutoff of >0.5 as previously published24 to define AR-active 
tumors. Because expression analysis of CTCs is not well established this transcriptional 
analysis will be performed only in metastatic biopsy tissue taken before treatment with 
Abiraterone Acetate 1000mg daily and at the time of initial treatment resistance. 
The probability of AR activity determined from the pretreatment biopsy and at the time of first 
progression with standard dose Abiraterone Acetate will be compared using a t statistic for 
paired data. The distributions of the probability values will be compared using the 
nonparametric Wilcoxon test for paired data. In addition, when the probability outcome is coded 
as a binary outcome and is dichotomized at the median at each time point, the agreement or 
change in AR activity will be analyzed using McNemar‟s chi square test of agreement for paired 
binary data. 
7.5.3 Metastatic Biopsy and CTC analysis 
Circulating tumor cells will be isolated for genetic analysis using the Vitatex VitaCap assay. 
Cells will be isolated from peripheral whole blood according to a published protocol for isolation 
of prostate cancer CTCs using this platform.25 Based on experience with this methodology it is 
expected that >90% of patients will have detectable CTCs, that yields will range from 150-750 
CTCs/ml, and that using a 40ml draw, adequate DNA suitable for downstream genomic 
analyses will be isolated from >70% of patients. Optional CTCs isolated using Veridex 
CellSearch and Epic Biosciences will be assayed in an exploratory fashion as well for 
enumeration purposes, to provide a control for the Vitatex analyses, and to explore the 
relationship of disease progresson with the presence of nuclear and cytoplasmic AR, presence 
of PTEN deletion, and expression of mesenchymal markers . Because Veridex CTCs are fixed 
using a preservative, no downstream genomic analyses will be performed on the Veridex 
CTCs. CTCs may also be sent to Xcell Biosciences for CTC culture in order to expand the 
population of cells available for genomic analysis and biologic characterization. All cultured 
CTCs and biomaterials will be returned to UCSF.  
The methylation status of specific promoter and intragenic CpG sites in CYP17A1 and in a 
predefined set of 20 genes involved in androgen synthesis from prior to the first dose of 
Abiraterone Acetate 1000mg daily to the time of post-treatment disease progression will be 
explored using paired pre and post-treatment biopsy samples and in CTCs. This analysis will 
take place in the Paris and Febbo labs at UCSF. Methylation will be assessed using an Illumina 
platform and will be expressed as a continuous variable as the β ratio of signal from a 
methylated probe relative to the sum of methylated and unmethylated probes at an individual 
site and as a binary categorical variable with presence defined using a conservative β ratio of 
>0.8. Descriptive statistics for continuous and binary variables will be calculated to summarize
the methylation state as well as the change from baseline post Abiraterone Acetate 1000mg
daily therapy for each gene from biopsy and CTC specimens. For binary outcomes this will
include the proportion of patients with methylation pre and/or post treatment for the 4
combinations and the proportion of patients with an increase in the number of methylation sites
in the gene body following treatment, each with 95% confidence intervals. For each gene

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considered as a continuous variable the mean baseline methylation β value and the mean 
difference from baseline post-treatment change will be reported with standard deviations and 
95% confidence intervals. A paired t statistic or the Wilcoxon matched pairs test will be used to 
test for a difference from pre to post-treatment in mean values or distributions, respectively. No 
adjustment for multiple comparisons will be made for these initial analyses of the relationship 
between methylation with ABI resistance. To summarize the results multivariable clustering 
analyses will be performed including genes identified to reflect change after ABI therapy in the 
univariate methods just described with at least a probability value <0.10. Hierarchical clustering 
may be used to explore relationships among the genes.  
8 
CRITERIA FOR PSA RESPONSE/PROGRESSION 
8.1 
PSA RESPONSE 
All patients will be evaluated for PSA response. Because it is possible that short-term 
increases in PSA will be followed by a meaningful response, PSA increases to Abiraterone 
Acetate during the first 12 weeks will not result in automatic discontinuation of therapy. The 
required sample size for this study is based upon the number of patients with progressive 
disease after achieving a PSA response of any magnitude after 12 weeks of treatment with 
standard-dose Abiraterone Acetate. Response to Abiraterone Acetate will be closely monitored 
to avoid over accrual. 
a) PSA Response: For patients receiving standard-dose therapy this is defined as a PSA
decline of any magnitude from baseline confirmed by a second measurement at least 2
weeks later. The reference for these declines should be a PSA measured within 2 weeks
prior to starting therapy. For patients receiving elevated-dose therapy PSA response is
defined as a ≥30% PSA decline from baseline after 12 weeks of elevated-dose therapy
b) PSA Progression: If any PSA decline from baseline has been achieved, PSA progression
occurs when the PSA has increased to at least 25% above the nadir and the increase in
the absolute-value PSA level is at least 2 ng/mL, or back to baseline, whichever is lower,
on at least 2 measurements at least 2 weeks apart. If no PSA decline has been achieved
then PSA progression occurs when the PSA has increased by at least 25% and the
increase in the absolute-value PSA level is at least 2 ng/mL after 12 weeks of therapy.
c) PSA Response Duration: For patients receiving standard-dose therapy the PSA response
duration commences on the date of the decline of any magnitude in PSA from baseline.
The response duration ends when the PSA value first increases by at least 25% above the
nadir, provided that the increase in the absolute-value PSA level is at least 2 ng/mL or back
to baseline, whichever is lower. For patients receiving elevated-dose therapy the PSA
response duration commences on the date of a ≥30% PSA from baseline. The response
duration ends when the PSA value first increases by at least 25% above the nadir, provided
that the increase in the absolute-value PSA level is at least 2 ng/mL or back to baseline,
whichever is lower.
d) Progressive Disease: Defined by PSA Progression OR RECIST defined criteria for
progressive disease OR the appearance of 2 new bone lesions on bone scan (note that for
the first assessment only a confirmatory scan performed 6 or more weeks later is required

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that shows a minimum of 2 or more new lesions) OR a new requirement for radiation 
therapy thought to be due to prostate cancer. 
e) Time to PSA Progression: The start of the time to PSA progression is the day treatment is
initiated. The end date is the first of the measurements determining progressive disease.
f)
Criteria for Definition of Progression #2. The criteria for defining progression #2 are the
same as for the definition of progression #1 however the PSA value at the time of progression
#1 will be the baseline for progression #2.
a. Example: Patient begins study with a PSA of 100, which declines to 40 ng/mL at
week 12, PD #1 will occur when PSA reaches 50 ng/mL or higher. Following dose-
increased Abiraterone Acetate therapy a “second PSA response” will be defined as
a decline below 35ng/ml and PD #2 will be defined as per standard criteria using 50
ng/mL as the baseline.
RECIST Criteria (Please see Appendix B) 
9 
REPORTING AND DOCUMENTATION OF ADVERSE EVENTS 
9.1 
Definitions 
9.1.1 Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a drug, without any judgment about causality. An adverse event can arise from any 
use of the drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
9.1.2 
Adverse Events of Special Interest  
Events that Janssen Services is actively monitoring as a result of a previously identified signal, 
including mineralocorticoid excess, cardiac adverse reactions, and liver toxicities. 
9.1.3 
 Adverse Reaction  
An adverse reaction means any adverse event caused by a drug.  Adverse reactions are a subset 
of all suspected adverse reactions for which there is reason to conclude that the drug caused the 
event. 
9.1.4   
Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between the drug and the 
adverse event.  A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 

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9.1.5 
Unexpected 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or package insert(s) or, is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not consistent with the 
risk information described in the general investigational plan or elsewhere in the current 
application.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure.  For example, a certain number of non-acute deaths in a cancer trial would be 
anticipated as an outcome of the underlying disease, but such deaths would generally not be listed 
as a suspected adverse reaction in the investigator brochure. 
Some adverse events are listed in the investigator brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation. Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class effect, 
the first case of angioedema observed with the drug under investigation should be considered 
unexpected for reporting purposes. 
9.1.6  
Serious 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
1. Death
2. A life-threatening adverse event
3. Inpatient hospitalization or prolongation of existing hospitalization
4. A persistent or significant incapacity or substantial disruption of the ability to conduct
normal life function
5. A congenital anomaly/birth defect
6. A suspected transmission of infectious agent by the study drug
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. 
9.1.7   
Life-threatening 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
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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.  
9.1.8  
J&J Medicinal Product 
The specific J&J drug under study and any other J&J medicinal product. 
9.1.9 
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. 
9.1.10 
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 J&J medicinal product

pregnancy exposure (maternal and paternal)

exposure to a medicinal product from breastfeeding

suspected abuse/misuse of a medicinal J&J product

inadvertent or accidental exposure to a medicinal J&J product
o
any failure of expected pharmacological action (i.e., lack of effect) of a J&J medicinal
product
o
unexpected therapeutic or clinical benefit from use of a Janssen Services medicinal
product
o
medication error involving a J&J product (with or without patient exposure to the
medicinal J&J product, e.g., name confusion)
o
Suspected transmission of any infectious agent via a medicinal product.
9.2 Management of Adverse Events, Serious Adverse Events and Special Reporting 
Situations 
For each subject, AEs SAEs, and Special Reporting Situations should be recorded after informed consent 
is obtained until the subject has completed participation in the study as follows: 
A Serious Adverse event or Special Reporting Situations must be reported if it occurs during a 
subject‟s participation in the Study (whether receiving Study Product or not) and within 30 days of 
receiving the last dose of Study Product. 
Any serious adverse event or Special Reporting Situations that is ongoing when a subject completes 
his/her participation in the Study must be followed until any of the following occurs: 
the event resolves or stabilizes;
the event returns to baseline condition or value (if a baseline value is available);
the event can be attributed to agents(s) other than the Study Product, or to factors unrelated to Study
conduct.
In general, the Principal Investigator must immediately report to JANSSEN SERVICES 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). 

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In that case, the investigator must immediately report the event to JANSSEN SERVICES. The 
Principal Investigator must record non-serious adverse events and report them to JANSSEN 
SERVICES according to the timetable for reporting as specified either in the protocol or to fulfill 
regulatory reporting requirements. 
9.3 Recording of Adverse Events, Serious Adverse Events and Special Reporting Situations 
All adverse events will be entered into OnCore®, UCSF‟s Clinical Trial Management System, 
whether or not the event is believed to be associated with use of the study drug.  Data about these 
events and their severity will be recorded using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) (V4.0), when applicable, on the appropriate case report forms (CRFs).  The 
Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore using the classification 
system listed below:  
Relationship 
Attribution 
Description 
Unrelated to 
investigational 
drug/intervention1 
Unrelated 
The AE is clearly NOT related to the 
intervention  
Unlikely 
The AE is doubtfully related to the intervention 
Related to 
investigational 
drug/intervention1 
Possible 
The AE may be related to the intervention  
Probable 
The AE is likely related to the intervention  
Definite 
The AE is clearly related to the intervention 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they are to be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions: 
Grade 0: 
 No AE (or within normal limits).  
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL). 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL. 
Grade 4: 
Life-threatening consequences; urgent intervention indicated. 
Grade 5: 
Death related to AE. 
9.4  Follow-up of Adverse Events 
All adverse events must be followed with appropriate medical management until resolved.  Patients 
removed from study for unacceptable adverse events will be followed until resolution or stabilization of 
the adverse event.  For selected adverse events for which administration of the investigational drug 
was stopped, a rechallenge of the subject with the investigational drug may be conducted if considered 
both safe and ethical by the Investigator.   

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9.5  Adverse Events Monitoring 
All adverse events, whether or not unexpected, and whether or not considered to be associated with 
the use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to the Data 
and Safety Monitoring Committee (DSMC), UCSF‟s Committee on Human Research (CHR), and, 
when the study is conducted under an Investigational New Drug Application (IND), to the Food and 
Drug Administration.   
All adverse events entered into OnCore® will be reviewed by the Site Committee on a monthly basis.  
The Site Committee will review and discuss at each monthly meeting the selected toxicity, the toxicity 
grade, and the attribution of relationship of the adverse event to the administration of the study drug(s). 
In addition, all adverse events and suspected adverse reactions considered “serious,” entered into 
OnCore® will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing 
basis and discussed at DSMC meetings which take place every six (6) weeks.   
9.6  Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee (DSMC) 
If a death occurs during the treatment phase of the study or within 30 days after the last administration 
of the study drug(s) and it is determined to be related either to the study drug(s) or to a study 
procedure, the Investigator or his/her designee must notify the DSMC Chair (or qualified alternate) 
within 24 business hours of knowledge of the event.  The contact may be by phone or e-mail. 
Reporting to UCSF’s Committee on Human Research (CHR) 
The Investigator must report events meeting the CHR definition of “Unanticipated Problem” (UP) within 
10 working days of his/her awareness of the event.  Guidance on Adverse Event Reporting to the CHR 
is available online at the UCSF Human Research Protection Program website.  
Expedited Reporting to the Food and Drug Administration (FDA) 
The Sponsor-Investigator is responsible for determining whether or not the suspected adverse reaction 
meets the criteria for expedited reporting in accordance with Federal Regulations (21 CFR §312.32).   
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all three 
definitions:  

Suspected adverse reaction (as defined in 9.1.4)

Unexpected (as defined in 9.1.5)

Serious (as defined in 9.1.6)
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
The timeframe for submitting an IND safety report to FDA is no later than 15 calendar days after the 
Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
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Any unexpected fatal or life-threatening suspected adverse reaction must be reported to FDA no  later 
than 7 calendar days after the Investigator‟s initial receipt of the information (21 CFR 312.32(c)(2)).  
Any relevant additional information that pertains to a previously submitted IND safety report  must be 
submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information is 
available (21 CFR 312.32(d)(2)).  
The investigator (or designee) should prepare Form FDA 3500A (MedWatch) detailing the event, and 
contact the Institutional Trials Unit for assistance in the preparation of the IND Safety Report.    
For additional information and guidance on IND Safety Reports, please refer to FDA‟s Guidance 
document Safety Reporting Requirements for INDs.  It is the Sponsor-Investigator‟s responsibility to 
meet regulatory requirements for expedited reporting. 
Reporting to Janssen Services 
All safety information (SAEs, Adverse Events of Special Interest, Special Reporting Situations, and 
Product Quality Complaints ) should be reported within 24 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. 
The following methods are acceptable for transmission of safety information to JANSSEN SERVICES: 

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, 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 non
functional).
10  DATA AND SAFETY MONITORING PLAN 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all HDF CCC 
institutional clinical studies.  A summary of DSMC activities for this study includes:  

Review of subject data

Review of suspected adverse reactions considered “serious”

Monitoring every six months (depending on study accrual)

Minimum of a yearly regulatory audit
10.1 
Monitoring and Reporting Guidelines 
All institutional Phase 2 therapeutic studies are designated with a moderate risk assessment.  The 
data is monitored every six months, with twenty percent of the subjects monitored (or at least three 
subjects if the calculated value is less than three).    

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The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF Coordinating 
Center will also coordinate quarterly conference calls with the participating sites to communicate the 
review of adverse events, safety data, and other study matters. 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  The 
Study Chair is responsible for the overall conduct of the study and for monitoring its safety and 
progress at all participating sites.  The Study Chair will conduct continuous review of data and subject 
safety and discuss each subject‟s treatment at monthly UCSF Site Committee meetings.  The 
discussions are documented in the UCSF Site Committee meeting minutes.   
Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and  organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF Coordinating 
Center will also coordinate, at minimum, quarterly conference calls with  the participating sites or 
more frequently as needed to discuss risk assessment.  The following issues will be discussed as 
appropriate: 

Enrollment information

Adverse Events (i.e. new adverse events and updates on unresolved adverse events and
new safety information)

Protocol Violations

Other issues affecting the conduct of the study
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating Center, 
as well as the participating sites.  The DSMC will be responsible for monitoring and query data entered 
in OnCore for the 20% of subjects it reviews at the UCSF Coordinating Center and the participating 
sites.  The data (i.e. copies of source documents) from the participating sites will be faxed over to the 
UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor the 
participating site‟s compliance with the protocol, patient safety, and to verify data entry. 
Adverse Event Review and Monitoring 
All adverse events, whether or not unexpected, and whether or not considered to be associated with 
the use of the study drug, will be entered into OnCore®, UCSF‟s Clinical Trial Management System.  
All adverse events entered into OnCore® will be reviewed on a monthly basis at the UCSF Site 
Committee meetings.  All clinically significant adverse events must be reported to the UCSF 
Coordinating Center by the participating sites within 10 business days of becoming aware of the event 
or during the next scheduled quarterly conference call, whichever is sooner.  The UCSF Site 
Committee will review and discuss the selected toxicity, the toxicity grade, and the attribution of 
relationship of the adverse event to the administration of the study drug(s) from the UCSF 
Coordinating Center  and the participating sites.  
In addition, all suspected adverse reactions considered “serious” must be entered in OnCore® and 
reported to the UCSF Coordinating Center within 1 business day.  The suspected adverse reactions 
considered “serious” will be reviewed and monitored by the Data and Safety Monitoring Committee on 
an ongoing basis and discussed at the DSMC meeting, which take place every six (6) weeks.  

 
 
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If a death occurs during the treatment phase of the study or within 30 days after the last administration 
of the study drug(s) and is determined to be related either to the investigational drug or any research 
related procedure, the Study Chair at the UCSF Coordinating Center or the assigned designee must 
be notified within 1 business day from the participating site(s) and the Study Chair must then notify 
the DSMC Chair or qualified alternate within 1 business day of this notification.  The contact may be by 
phone or e-mail. 
 
Increase in Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, a report should be submitted to the 
DSMC at the time the increased rate is identified.  The report will indicate if the incidence of AEs 
observed in the study is within the range stated in the Investigator Brochure or package insert.   
 
If at any time the Study Chair stops enrollment or stops the study due to safety issues the DSMC Chair 
and administrator must be notified within 1 business day via e-mail.  The DSMC must receive a 
formal letter within 10 business days and the CHR must be notified. 
 
Data and Safety Monitoring Committee Contacts: 
 
DSMC Chair: 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
11 STUDY MANAGEMENT 
11.1  Prestudy Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements. 
 
Before initiating this trial, the Investigator will have written and dated approval from the Institutional 
Review Board for the protocol, written informed consent form, subject recruitment procedures (e.g., 
advertisements), and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.   
 
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a letter 
from FDA stating that the study is exempt from IND requirements.  
 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 

 
 
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requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory 
requirements. 
 
11.2 Institutional Review Board 
 
The protocol, the proposed informed consent form, and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
Committee on Human Research (CHR) (UCSF‟s IRB).  Prior to obtaining CHR approval, the protocol 
must be approved by the Helen Diller Family Comprehensive Cancer Center Site Committee and by 
the Protocol Review Committee (PRC).  The initial protocol and all protocol amendments must be 
approved by the IRB prior to implementation.   
 
11.3    Informed Consent 
 
All participants must be provided a consent form describing the study with sufficient information for 
participants to make an informed decision regarding their participation.  Participants must sign the IRB-
approved informed consent form prior to participation in any study specific procedure.  The participant 
must receive a copy of the signed and dated consent document.  The original signed copy of the 
consent document must be retained in the medical record or research file.  
 
11.4 Changes in the Protocol 
 
Once the protocol has been approved by the UCSF Committee on Human Research (CHR), any 
changes to the protocol must be documented in the form of an amendment.  The amendment must be 
signed by the Investigator and approved by PRC and the CHR prior to implementation.   
 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after implementation. 
 
 
11.5 Handling and Documentation of Clinical Supplies 
The Investigator shall maintain complete records showing the receipt, dispensation, return, or other 
disposition of all investigational drugs.  The date, quantity and batch or code number of the drug, and 
the identification of patients to whom study drug has been dispensed by patient number and initials will 
be included.  The sponsor-investigator will maintain written records of any disposition of the study 
drug. 
 
The Investigator shall not make the investigational drug available to any individuals other than to 
qualified study patients.  Furthermore, the Investigator will not allow the investigational drug to be used 
in any manner other than that specified in this protocol. 
 
11.6 Case Report Forms (CRFs) 
 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 
Report Forms (CRFs) will document treatment outcomes for data analysis.  All study data will be 
entered into OnCore®, UCSF‟s Clinical Trial Management System (CTMS) via standardized CRFs in 
accordance with the CTMS study calendar, using single data entry with a secure access account.  The 

 
 
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Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible upon completion of 
the study visit; the Investigator will review and approve the completed CRFs.  
 
Each participating site will complete study specific CRFs for safety monitoring and data analysis.  Each 
site will enter the study data into OnCore® via standardized CRFs in accordance with the CTMS study 
calendar, using single data entry with a secure access account. The participating site‟s Clinical 
Research Coordinator (CRC) will complete the CRFs; the Investigator will review and approve the 
completed CRFs – this process must be completed within 3 business days of the visit. Study data from 
the participating site will be reported and reviewed in aggregate with data from patients enrolled at the 
coordinating center, UCSF.  All source documentation and CTMS data will be available for 
review/monitoring as needed. 
 
The information collected on CRFs shall be identical to that appearing in original source documents.  
Source documents will be found in the patient‟s medical records maintained by UCSF personnel.  All 
source documentation should be kept in separate research folders for each patient. 
 
In accordance with federal regulations, the Investigator is responsible for the accuracy and authenticity 
of all clinical and laboratory data entered onto CRFs.  Each CRF must be reviewed for accuracy by the 
Investigator, corrected as necessary, and then approved.  Alternatively, the Investigator may sign 
individual, printed CRFs.  These signatures attest that the information contained on the CRFs is true 
and accurate.  
 
All source documentation and CTMS data will be available for review/monitoring by the Data and 
Safety Monitoring Committee (DSMC) and regulatory agencies. 
 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At study 
completion, when the database has been declared to be complete and accurate, the database will be 
locked.  Any changes to the database after that time can only be made by joint written agreement 
among the Principal Investigator, the Trial Statistician, and the Protocol Project Manager. 
 
 
 
11.7 Oversight and Monitoring Plan 
 
The Helen Diller Family Comprehensive Cancer Center Data and Safety Monitoring Committee 
(DSMC) will be the monitoring entity for this study.  The DSMC will monitor the study in accordance 
with the NCI-approved Data and Safety Monitoring Plan (DSMP).  The DSMC will regularly review all 
adverse events and suspected adverse reactions considered “serious” and protocol deviations 
associated with the research to ensure the protection of human subjects.  The DSMC will audit study-
related activities to ensure that the study is conducted in accordance with the protocol, local standard 
operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant results of the 
DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as applicable.   
11.8   Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF Coordinating 
Center will also coordinate, at minimum, biweekly conference calls with the participating sites for 
Phase I dose escalation studies prior to each cohort escalation and at the completion of each cohort or 

 
 
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more frequently as needed to discuss risk assessment.  The following issues will be discussed as 
appropriate: 
 
Enrollment information  
 
Cohort updates (i.e. DLTs) 
 
Adverse events (i.e. new adverse events and updates on unresolved adverse events and new 
safety information) 
 
Protocol violations 
 
Other issues affecting the conduct of the study 
11.9  Record Keeping and Record Retention 
The investigator is required to maintain adequate records of the disposition of the drug, including 
dates, quantity, and use by subjects, as well as written records of the disposition of the drug when the 
study ends.   
 
The investigator is required to prepare and maintain adequate and accurate case histories that record 
all observations and other data pertinent to the investigation on each individual administered the 
investigational drug or employed as a control in the investigation. Case histories include the case 
report forms and supporting data including, for example, signed and dated consent forms and medical 
records including, for example, progress notes of the physician, the individual's hospital chart(s), and 
the nurses' notes. The case history for each individual shall document that informed consent was 
obtained prior to participation in the study. 
 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it is 
being investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified. 
11.10  Coordinating Center Documentation of Distribution 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution of 
study documents as well as their receipt (when possible). The HDFCCC recommends that the Study 
Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, drug 
manufacturer, participating sites, etc.). 
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover letters, 
amendment outlines (summary of changes), etc., along with distribution documentation and (when 
available) documentation of receipt. 
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received. 
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed. 

 
 
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11.11 Regulatory Documentation 
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the UCSF 
Committee on Human Research (CHR). Prior to implementing this protocol at the participating sites, 
approval for the UCSF CHR approved protocol must be obtained from the participating site‟s IRB.  
The following documents must be provided to UCSF HDFCCC before the participating site can be 
initiated and begin enrolling participants:  
 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization  
 
Participating Site IRB approved consent form  
 
Participating Site IRB membership list  
 
Participating Site IRB‟s Federal Wide Assurance number and OHRP Registration number  
 
Curriculum vitae and medical license for each investigator and consenting professional  
 
Documentation of Human Subject Research Certification training for investigators and key staff 
members at the Participating Site  
 
Participating site laboratory certifications and normals  
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment. 
 

 
 
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12 References:  
 
1. 
Culig Z, Stober J, Gast A, et al: Activation of two mutant androgen receptors from 
human prostatic carcinoma by adrenal androgens and metabolic derivatives of testosterone. Cancer 
detection and prevention 20:68-75, 1996 
 
2. 
Tan J, Sharief Y, Hamil KG, et al: Dehydroepiandrosterone activates mutant androgen 
receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and 
LNCaP cells. Molecular endocrinology 11:450-9, 1997 
 
3. 
Hellerstedt BA, Pienta KJ: The current state of hormonal therapy for prostate cancer. 
CA: a cancer journal for clinicians 52:154-79, 2002 
 
4. 
Chen CD, Welsbie DS, Tran C, et al: Molecular determinants of resistance to 
antiandrogen therapy. Nature medicine 10:33-9, 2004 
 
5. 
Mostaghel EA, Page ST, Lin DW, et al: Intraprostatic androgens and androgen-
regulated gene expression persist after testosterone suppression: therapeutic implications for 
castration-resistant prostate cancer. Cancer research 67:5033-41, 2007 
 
6. 
Small EJ, Halabi S, Dawson NA, et al: Antiandrogen withdrawal alone or in combination 
with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22:1025-33, 
2004 
 
7. 
Loose DS, Kan PB, Hirst MA, et al: Ketoconazole blocks adrenal steroidogenesis by 
inhibiting cytochrome P450-dependent enzymes. The Journal of clinical investigation 71:1495-9, 1983 
 
8. 
Rowlands MG, Barrie SE, Chan F, et al: Esters of 3-pyridylacetic acid that combine 
potent inhibition of 17 alpha-hydroxylase/C17,20-lyase (cytochrome P45017 alpha) with resistance to 
esterase hydrolysis. Journal of medicinal chemistry 38:4191-7, 1995 
 
9. 
O'Donnell A, Judson I, Dowsett M, et al: Hormonal impact of the 17alpha-
hydroxylase/C(17,20)-lyase inhibitor Abiraterone Acetate (CB7630) in patients with prostate cancer. 
British journal of cancer 90:2317-25, 2004 
 
10. 
Attard G, Reid AH, A'Hern R, et al: Selective inhibition of CYP17 with Abiraterone 
Acetate is highly active in the treatment of castration-resistant prostate cancer. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 27:3742-8, 2009 
 
11. 
Ryan CJ, Smith MR, Fong L, 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. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 28:1481-8, 2010 
 
12. 
Ryan CJ, Shah S, Efstathiou E, et al: Phase II study of Abiraterone Acetate in 
chemotherapy-naive metastatic castration-resistant prostate cancer displaying bone flare discordant 
with serologic response. Clinical cancer research : an official journal of the American Association for 
Cancer Research 17:4854-61, 2011 
 
13. 
Danila DC, Morris MJ, de Bono JS, et al: Phase II multicenter study of Abiraterone 
Acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 28:1496-501, 
2010 
 
14. 
de Bono JS, Logothetis CJ, Molina A, et al: Abiraterone Acetate and increased survival 
in metastatic prostate cancer. The New England journal of medicine 364:1995-2005, 2011 
 
15. 
Attard G, Reid AH, de Bono JS: Abiraterone Acetate is well tolerated without 
concomitant use of corticosteroids. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 28:e560-1; author reply e562, 2010 
 
16. 
Stanbrough M, Bubley GJ, Ross K, et al: Increased expression of genes converting 
adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 66:2815-25, 
2006 

 
 
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17. 
Ryan CJ, Halabi S, Ou SS, et al: 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 13:2030-7, 2007 
 
18. 
Attard G, Reid AH, Yap TA, et al: Phase I clinical trial of a selective inhibitor of CYP17, 
Abiraterone Acetate, confirms that castration-resistant prostate cancer commonly remains hormone 
driven. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
26:4563-71, 2008 
 
19. 
Collette L, Burzykowski T, Schroder FH: Prostate-specific antigen (PSA) alone is not an 
appropriate surrogate marker of long-term therapeutic benefit in prostate cancer trials. European 
journal of cancer 42:1344-50, 2006 
 
20. 
Scher HI, Halabi S, Tannock I, et al: Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate 
Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 26:1148-59, 2008 
 
21. 
Carey AH, Waterworth D, Patel K, et al: Polycystic ovaries and premature male pattern 
baldness are associated with one allele of the steroid metabolism gene CYP17. Human molecular 
genetics 3:1873-6, 1994 
 
22. 
Stanford JL, Noonan EA, Iwasaki L, et al: A polymorphism in the CYP17 gene and risk 
of prostate cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American 
Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 
11:243-7, 2002 
 
23. 
Hamada A, Danesi R, Price DK, et al: Association of a CYP17 polymorphism with 
overall survival in Caucasian patients with androgen-independent prostate cancer. Urology 70:217-20, 
2007 
 
24. 
Mendiratta P, Mostaghel E, Guinney J, et al: Genomic strategy for targeting therapy in 
castration-resistant prostate cancer. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 27:2022-9, 2009 
 
 

 
 
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13  APPENDICES 
Appendix A NCI CTC Common Toxicity Criteria 
V4.0 (CTCAE): publish date May 28, 2009: 
http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-
15_QuickReference_5x7.pdf

 
 
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Appendix B 
RESPONSE EVALUATION CRITERIA in SOLID TUMORS 
(RECIST) 
Eligibility 
 
Only patients with measurable disease at baseline should be included in protocols where objective 
tumor response is the primary endpoint.  
Measurable disease - the presence of at least one measurable lesion. If the measurable disease 
is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
Measurable lesions - lesions that can be accurately measured in at least one dimension with 
longest diameter 20 mm using conventional techniques or 10 mm with spiral CT scan. 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed by 
imaging techniques; and. 
 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. 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.  
 
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. 
Methods of Measurement  
 
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI 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. 
 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should 
not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. US 
might also be useful to confirm the complete disappearance of superficial lesions usually assessed 
by clinical examination. 
 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been fully 
and widely validated. Their uses in this specific context require sophisticated equipment and a high 
level of expertise that may only be available in some centers. Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation purposes in specialized 

 
 
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centers. However, such techniques can be useful in confirming complete pathological response 
when biopsies are obtained. 
 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions and residual malignant lesions in tumor 
types such as germ cell tumors). 
Baseline documentation of “Target” and “Non-Target” lesions 
 
All measurable lesions up to a maximum of five 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 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 reference by which to characterize the 
objective tumor. 
 
All other lesions (or sites of disease) 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 throughout follow-up.  
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 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 
* 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 
 
Evaluation of non-target lesions 
* Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level 
* Incomplete Response/ Stable 
Disease (SD):  
Persistence of one or more non-target lesion(s) or/and maintenance 
of tumor marker level above the normal limits 
* Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions (1)  
(1) 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 later on by the review 
panel (or study chair). 

 
 
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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 PD the smallest measurements recorded since the 
treatment started). In general, the patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria  
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be classified as having “symptomatic deterioration”. 
Every effort should be made to document the objective progression even after discontinuation of treatment.  
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends on this determination, it is recommended that the residual lesion 
be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
Confirmation 
 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed.  In cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome of such studies that the responses are not confirmed. 
 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for response 
are first met. Longer intervals as determined by the study protocol may also be appropriate.  
In the case of SD, follow-up measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the study protocol. 
 
 
 
 

 
 
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Appendix C 
PROSTATE CANCER WORKING GROUP 2 CRITERIA  
Variable 
PCWG2 
PSA 
Recognize that a favorable effect on PSA may be delayed for 12 weeks or more, even for a 
cytotoxic drug 
 
Monitor PSA by cycle but plan to continue through early rises for a minimum of 12 weeks 
unless other evidence of progression 
 
Ignore early rises (prior to 12 weeks) in determining PSA response 
 
For control/relieve/eliminate end points: 
 
Record the percent change from baseline (rise or fall) at 12 weeks, and separately, the 
maximal change (rise or fall) at any time using a waterfall plot 
 
Progression: 
 
Decline from baseline: record time from start of therapy to first PSA increase that is ≥ 25% 
and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value 3 or more weeks 
later (i.e., a confirmed rising trend)  
 
The requirement of an increase of 5 ng/mL is decreased to 2 ng/mL, and the requirement for 
a 50% increase is reduced to 25% 
 
Recording the duration of PSA decline of little value 
 
No decline from baseline: 
 
PSA progression ≥ 25% and ≥ 2 ng/mL after 12 weeks 
Soft-tissue 
lesions 
For control/relieve/eliminate end points: 
 
Use RECIST with caveats 
 
    Only report changes in lymph nodes that were ≥ 2 cm in diameter at baseline 
 
    Record changes in nodal and visceral soft tissue sites separately 
 
    Record complete elimination of disease at any site separately 
 
    Confirm favorable change with second scan 
 
    Record changes using waterfall plot 
 
For delay/prevent end points: 
 
Use RECIST criteria for progression, with additional requirement that progression at first 
assessment be confirmed by a second scan 6 or more weeks later 
 
Note that for some treatments, a lesion may increase in size before it decreases 
Bone 
For control/relieve eliminate end points: 
 
Record outcome as new lesions or no new lesions 
 
First scheduled reassessment: 
 
No new lesions: continue therapy 
 
New lesions: perform a confirmatory scan 6 or more weeks later 
 
Confirmatory scan: 
 
No new lesions: continue therapy 
 
Additional new lesions: progression 
 
Subsequent scheduled reassessments: 
 
No new lesions: continue 

 
 
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Variable 
PCWG2 
 
New lesions: progression 
 
For prevent/delay end points (progression): 
 
The appearance of ≥ 2 new lesions, and, for the first reassessment only, a confirmatory scan 
performed 6 or more weeks later that shows a minimum of 2 or more additional new lesions 
 
The date of progression is the date of the first scan that shows the change 
Symptoms 
Consider independently of other outcome measures 
 
Document pain and analgesia at entry with a lead in period and measure repeatedly at 3- to 
4-week intervals 
 
Perform serial assessments of global changes in health related quality of life (HRQOL), 
urinary or bowel compromise, pain management, additional anticancer therapy 
 
Ignore early changes (≤ 12 weeks) in pain or HRQOL in absence of compelling evidence of 
disease progression 
 
Confirm response or progression of pain or HRQOL end points ≥ 3 weeks later 
 

 
 
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Appendix D 
Drug Diaries 
 
Standard Dose (1,000 mg daily) 
  
Dose Increased (1,000 mg twice a day) 
 

 
 
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Appendix E 
Prohibited Concomitant Medications 
 
Drug Type 
Generic Drug Name 
Brand Name 
Hormonal Therapy 
Bicalutamide 
Casodex, Cosudex, Calutide, 
Kalumid 
 
Nilutamide 
Nilandron or Anandron 
 
Flutamide 
Eulexin or Flutamin 
 
Cyproterone acetate 
Androcur, 
Cyprostat,Cyproteron, Procur, 
Cyprone, Cyprohexal, 
Ciproterona, 
Cyproteronum,Neoproxil, 
Siterone 
 
Enzalutamide 
Xtandi 
 
ARN-509 
 
 
Finasteride 
Proscar, Propecia 
 
Dutasteride 
Avodart 
 
Spironolactone 
Aldactone, Novo-Spiroton, 
Aldactazide, Spiractin, 
Spirotone, Verospiron or 
Berlactone 
 
Megestrol acetate 
Megace 
 
Diethylstilbestrol (DES) 
Stilbestrol, Stilboestrol, Honvol 
 
Herbal Mixture 
PC-SPES 
 
Herbal Mixture 
PC-Hope 
 
Herb 
Saw Palmetto 
 
Ketoconazole 
Nizoral 
 
TAK-700 
Orteronel 
 
TOK-001 
 
Immune therapy 
Provenge, Ipilumumab, 
ProstVac 
Sipuleucel-T, Yervoy, 
ProstVac 
 
GM-CSF 
Sargramostim, Leukine 
Chemotherapy 
Docetaxel 
Taxotere 
 
Mitoxantrone 
Novantrone 
 
Vinorelbine 
Navelbine 
 
Estramustine 
Emcyt 

 
 
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Ixabepilone 
Ixempra 
 
Cabazitaxel 
Jevtana 
Radiotherapy 
Strontium 
Metastron 
 
Samarium 
Quadramet 
 
Radium-223 
Alpharadin 
Drug-drug 
interactions 
Phenytoin 
Dilantin 
 
Carbamazepime 
Tegretol 
 
Rifampin 
Rifadin, Rimactane 
 
Rifabutin 
Mycobutin 
 
Rifapentine 
Priftin 
 
Phenobarbital 
Luminal 
 
Itraconazole 
Sporanox 
 
Clarithromycin 
Biaxin 
 
Atazanivir 
Reyataz 
 
Nefazodone 
Serzone 
 
Saquinavir  
Invirase 
 
Telithromycin 
Ketek 
 
Ritonavir 
Norvir 
 
Indinavir 
Crixivan 
 
Nelfinavir 
Viracept 
 
Voriconazole 
Vfend 
 
Thioridazine 
Mellaril 
 
Dextromethorphan 
Robitussin, NyQuil