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 (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.