A Phase II Study of Increased-Dose Abiraterone Acetate in Patients With Castration Resistant Prostate Cancer

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 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 not achieving a greater than or equal to 30% 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 an initial greater than or equal to 30% PSA decline
(referred to as Progressive Disease (PD) #1), subjects will begin taking Abiraterone Acetate
1000 mg po BID. Patients will continue to take prednisone 5mg BID and will continue this
therapy until a second progression at which point they will be withdrawn from the study.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.

Inclusion Criteria:

- 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

- Be willing/able to adhere to the prohibitions and restrictions specified in this
protocol

- Written Authorization for Use and Release of Health and Research Study Information
has been obtained

- Male aged 18 years and above

- Able to swallow the study drug whole as a tablet

- Willing to take abiraterone acetate on an empty stomach; no food should be consumed
at least two hours before and for at least one hour after the dose of abiraterone
acetate is taken

- Patients who have partners of childbearing potential must be willing to use a method
of birth control with adequate barrier protection as determined to be acceptable by
the principal investigator and sponsor during the study and for 1 week after last
study drug administration.

- Have a baseline serum potassium of ≥ 3.5 mEq/L

- Have aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin
levels < 1.5 x ULN

- Have a serum albumin of ≥ 3.0 g/dL

- 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)

- Have a platelet count of ≥ 100,000/μL

- Have an absolute neutrophil count of > 1500 cell/mm3

- Have a calculated creatinine clearance ≥ 60 mL/min

- Have a hemoglobin of ≥ 9.0 g/dL

- Have histologically confirmed adenocarcinoma of the prostate.

- No prior therapy with chemotherapy for metastatic prostate cancer.

- Have metastatic disease based on a positive bone scan or objective imaging on CT
scan.

- 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.

- Testosterone < 50 ng/dL.

- Progressive disease after androgen deprivation: PSA evidence for progressive prostate
cancer 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. If the confirmatory PSA value is less
than the screening PSA value, then an additional test for rising PSA will be required
to document progression.

- Antiandrogen Withdrawal Patients who are receiving an antiandrogen as part of primary
androgen ablation must demonstrate disease progression following discontinuation of
antiandrogen.

- 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.

- For patients receiving flutamide, at least one of the PSA values must be obtained 4
weeks or more after flutamide discontinuation.

- For patients receiving bicalutamide or nilutamide, at least one of the PSA values
must be obtained 6 weeks or more after antiandrogen discontinuation.

- 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.

- ECOG Performance Status 0-1

- Life expectancy of ≥ 12 weeks.

Exclusion Criteria:

- Active infection or other medical condition that would make prednisone/prednisolone
(corticosteroid) use contraindicated

- Known brain metastasis

- 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

- Active or symptomatic viral hepatitis or chronic liver disease

- History of pituitary or adrenal dysfunction

- Clinically significant heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or New
York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction
measurement of < 50 % at baseline

- Atrial Fibrillation, or other cardiac arrhythmia requiring medical therapy

- Administration of an investigational therapeutic within 30 days of screening

- Have poorly controlled diabetes

- Have a history of gastrointestinal disorders (medical disorders or extensive surgery)
that may interfere with the absorption of the study agents

- Have a pre-existing condition that warrants long-term corticosteroid use in excess of
study dose

- Have known allergies, hypersensitivity, or intolerance to abiraterone acetate or
prednisone or their excipients

- Any condition which, in the opinion of the investigator, would preclude participation
in this trial.

- Pure small cell carcinoma of the prostate or any mixed histology cancer of the
prostate (eg: neuroendocrine) which contains < 50% adenocarcinoma.

- 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.

- Prior therapy with Abiraterone Acetate or other CYP17 inhibitor(s) including TAK-700
or TOK-001, or investigational agent(s) targeting the androgen receptor for
metastatic prostate cancer.

- Prior therapy with ketoconazole for > 2 weeks for prostate cancer.

- Therapy with supplements or complementary medicines/botanicals within 4 weeks of
first dose of study drug, except for any combination of the following:

- Conventional multivitamin supplements

- Selenium

- Lycopene

- Soy supplements

- Prior radiation therapy completed < 4 weeks prior to enrollment

- 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.

- 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.

- Active psychiatric illnesses/social situations that would limit compliance with
protocol requirements.

- Patients in whom urgent chemotherapy, in the opinion of the treating physician, is
indicated should not be enrolled in this study.