A Phase II Study of Increased-Dose Abiraterone Acetate in Patients With Castration Resistant Prostate Cancer
A Phase II Study of Increased-Dose Abiraterone Acetate in Patients With Castration Resistant Prostate Cancer
The purpose of this study is to find out what effects, good and/or bad,an increased dose of
 Abiraterone Acetate in combination with prednisone has on patients and their prostate cancer.
 This study will investigate whether an increased-dose (2,000mg daily) is safe and potentially
 effective when given to patients whose cancer has grown while taking the standard dose.
This is a phase II multicenter trial of Abiraterone Acetate (AA) 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 single-nucleotide polymorphisms (SNP) 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 androgen receptor
 (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. Prostate-specific antigen (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
 twice a day (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 milliequivalents per litre (mEq/L)

 -  Have aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin
 levels < 1.5 x upper limit of normal (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 Luteinizing hormone-releasing
 hormone (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 (AAWD): 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
 patients without PSA decline on an anti-androgen or in those in whom a PSA response
 lasted < 3 months.

 -  Eastern Cooperative Oncology Group (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.