Abiraterone Acetate in Patients With Prostate Cancer Who Have Failed Hormone Therapy

• Serum blood levels of testosterone [ Time Frame: Every 7 days in the first 2 cycles and then at the end of Cycles 3, 4, 5, and 6 in Phase 1; end of Cycles 1, 3, and 6 in Phase 2; and at the time of disease progression ] [ Designated as safety issue: No ]
• Number of patients with adverse events [ Time Frame: Up to 28 days after the last dose of study drug ] [ Designated as safety issue: Yes ]
• Serum blood levels of testosterone precursors [ Time Frame: Every 7 days in the first 2 cycles and then at the end of Cycles 3, 4, 5, and 6 in Phase 1; end of Cycles 1, 3, and 6 in Phase 2; and at the time of disease progression ] [ Designated as safety issue: No ]
• Duration of response for prostate specific antigen [ Time Frame: Up to 12 cycles of treatment ] [ Designated as safety issue: No ]
• Objective tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 12 cycles of treatment ] [ Designated as safety issue: No ]
• Duration of objective tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 12 cycles of treatment ] [ Designated as safety issue: No ]
• Time to disease progression [ Time Frame: Up to 12 cycles of treatment ] [ Designated as safety issue: No ]
• Time to prostate cancer pain progression [ Time Frame: Up to 12 cycles of treatment ] [ Designated as safety issue: No ]
• Number of patients with changes in biochemical bone markers [ Time Frame: After Cycles 2, 4, 8, and 12 ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: Up to 12 cycles of treatment ] [ Designated as safety issue: No ]
• Mean plasma concentrations of abiraterone [ Time Frame: Pre-dose and post-dose Cycles 1, 2, 3, 4, 7, 10, and the time of disease progression ] [ Designated as safety issue: No ]
• Maximum plasma concentrations of abiraterone [ Time Frame: Pre-dose and post-dose Cycles 1, 2, 3, 4, 7, 10, and the time of disease progression ] [ Designated as safety issue: No ]
• Time to reach the maximum plasma concentration of abiraterone [ Time Frame: Pre-dose and post-dose Cycles 1, 2, 3, 4, 7, 10, and the time of disease progression ] [ Designated as safety issue: No ]
• Area under the plasma-concentration-time curve from time 0 to the last quantifiable concentration of abiraterone [ Time Frame: Pre-dose and post-dose Cycles 1, 2, 3, 4, 7, 10, and the time of disease progression ] [ Designated as safety issue: No ]
• Area under the plasma-concentration-time curve from time 0 to infinite time of abiraterone [ Time Frame: Pre-dose and post-dose Cycles 1, 2, 3, 4, 7, 10, and the time of disease progression ] [ Designated as safety issue: No ]
• Elimination half-life associated with the terminal slope of the semilogarithmic drug concentration-time curve of abiraterone [ Time Frame: Pre-dose and post-dose Cycles 1, 2, 3, 4, 7, 10, and the time of disease progression ] [ Designated as safety issue: No ]
• Time to last quantifiable plasma concentration of abiraterone [ Time Frame: Pre-dose and post-dose Cycles 1, 2, 3, 4, 7, 10, and the time of disease progression ] [ Designated as safety issue: No ]

The purpose of this study is to determine the maximum tolerated dose and evaluate the safety, tolerability, and activity at the recommended dose (maximum tolerated dose) of abiraterone acetate in patients with hormone refractory prostate cancer (HRPC).

This is an open-label (identity of study drug will be known) study to evaluate the safety, tolerability, and recommended dose of abiraterone acetate (referred to as abiraterone) taken orally (by mouth), once daily in patients with hormone refractory prostate cancer (HRPC). The study will consist of a dose escalation stage (Phase 1) that will be conducted to determine the maximum tolerated dose (MTD) of abiraterone and an activity evaluation stage (Phase 2) to evaluate the activity of abiraterone in patients with HRPC. Abiraterone acetate (also known as CB7630) is a drug that suppresses the synthesis of testosterone. Abiraterone will be taken orally once daily. Single doses of abiraterone (starting at 250 mg up to a maximum of 2000 mg) will be taken for 28-day treatment periods to determine the MTD. Patients will take MTD of abiraterone for up to twelve 28 day cycles (12 months).

• Drug: Phase 1: abiraterone acetate
  Abiraterone 250 mg (1 capsule) up to 2000 mg (8 capsules) once daily, each dose tested in sequential order for 28 days to determine the MTD.
• Drug: Phase 2: abiraterone acetate
  Phase 1 MTD for twelve 28-day cycles (12 months).

Inclusion Criteria:

• Histologically documented adenocarcinoma of the prostate, clinically refractory or resistant to hormone therapy, as documented by progression following at least one hormonal therapy, which must include orchiectomy or ongoing treatment with gonadotropin releasing hormone (GnRH) agonists
• Prostate specific antigen (PSA) evidence for progressive prostate cancer
• Patients who were withdrawn from anti-androgen therapy less than 6 months prior to inclusion in the study require one PSA higher than the last pre-withdrawal PSA or 2 increases in PSA documented after the post-withdrawal nadir >=4 weeks from treatment withdrawal if treated with flutamide and >=6 weeks if treated with bicalutamide or nilutamide
• Eastern Cooperative Oncology Group (ECOG) performance status score = 0-1
• Laboratory values within protocol-defined parameters
• Systolic blood pressure <160 and diastolic blood pressure <100 mmHg documented on at least 3 different days
• Ongoing gonadal androgen deprivation therapy with luteinizing hormone-releasing hormone (LHRH) analogues or orchiectomy
• Castrate testosterone level <50 ng/dl or <2.00 nmol/L (nmol/L x 28.8 = ng/dL)
• Normal baseline adrenocorticotropic hormone (ACTH) stimulation test (this criteria will be removed if no evidence of adrenocortical insufficiency is observed in the dose escalation phase)
• Life expectancy of >=12 weeks
• Agrees to protocol-defined use of effective contraception

Exclusion Criteria:

• Prior cytotoxic chemotherapy for prostate cancer (including estramustine, docetaxel and mitoxantrone). All other systemic chemotherapy must have been completed at least 2 years prior to enrollment
• Prior therapeutic radionucleotide therapy (except Radium 223) for prostate cancer
• Local therapy including external beam radiotherapy, brachytherapy, cryotherapy, or high-intensity focused ultrasound to the prostate bed within 4 weeks of start of study
• Prior ketoconazole, aminoglutethimide, or treatment with any investigational anticancer agent, including systemic corticosteroids for the treatment of prostate cancer, within 4 weeks of start of study
• Patients receiving any other hormonal therapy, including any dose of megestrol acetate (Megace), Proscar (finasteride), any herbal product known to decrease PSA levels (eg, saw palmetto and PC-SPES), or any systemic corticosteroid must discontinue the agent for at least 4 weeks prior to enrollment
• Treatment with any investigational anticancer agent within 4 weeks of start of study.
• Patients on stable doses of bisphosphonates that show subsequent tumour progression may continue on this medication; however, patients are not allowed to initiate bisphosphonate therapy within two weeks prior to starting therapy or throughout the study
• No supplements or complementary medicines/botanicals are permitted while on protocol therapy, except for any combination of the following: conventional multivitamin supplements, selenium, soy supplements
• Patients with serious or uncontrolled co-existent non-malignant diseases, or active or uncontrolled infection
• Patients with central nervous system disease and/or brain metastases
• No currently active second malignancy other than non-melanoma skin cancer
• Clinical and/or biochemical evidence of hyperaldosteronism
• Patients with well controlled hypertension requiring medication will be allowed after the dose escalation stage is completed
• NYHA Class III or IV congestive heart failure
• Myocardial infarction within the 6 months prior to start of study
• No active or uncontrolled autoimmune disease that may require corticosteroid therapy during protocol treatment
• Major surgery or significant traumatic injury within 4 weeks of start of study