A Safety Study of Abiraterone Acetate Administered in Combination With Docetaxel in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC)

This is an open-label (patients and their doctors will know the identity of study drug
administered), uncontrolled (patients are not assigned to treatment by chance), multicenter
safety study of escalating dose levels of abiraterone acetate administered in combination
with docetaxel plus prednisone in patients with metastatic castration-resistant prostate
cancer (mCRPC). This study is conducted in 2 parts. Part I consists of Screening, Treatment,
assessment of dose-limiting toxicity (DLT), and determination of the maximum tolerated dose
(MTD). Participants are enrolled in sequential 6-subject cohorts (groups) and administered
combination therapy (abiraterone acetate and docetaxel plus prednisone) according to a
dose-escalation schedule. The abiraterone acetate dose in this study will escalate from 500
mg to 1000 mg daily until the MTD is determined. The MTD is the highest combination dose
among the dose combinations investigated in this study at which no more than 2 (33%) of the
patients in a cohort experience a DLT. A DLT is defined by an adverse event occurring from
Day 1 Week 2 (first dose of abiraterone acetate) to the day before the Day 1 Week 7 docetaxel
infusion (3 weeks after the second docetaxel infusion); non-hematological toxicity >=Grade 3;
Grade 4 neutropenia lasting more than 5 days, neutropenia complicated by fever, or systemic
infection; thrombocytopenia <25,000/mcL, or any thrombocytopenia requiring platelet
transfusion; and, any subjectively intolerable toxicity. Part II of the study consists of
Continuing Treatment, when patients remain at the allocated dose level, escalate to the
combination MTD, or discontinuation of docetaxel (if toxicity or intolerability develops) and
continue abiraterone acetate (up to 1000 mg/day) plus prednisone, until disease progression;
End of Treatment, when posttreatment efficacy and safety will be documented; and Follow-Up,
when survival status and new antitumor therapy are monitored. Blood samples for
pharmacokinetic and efficacy measurements will be collected at selected times during the
study. Safety will be monitored. The total duration of study participation may be up to 36
months. Oral abiraterone acetate will be administered as a single daily dose (500, 750, or
1000 mg). Docetaxel will be administered once every 3 weeks as an intravenous (IV) infusion
(60 or 75 mg/m2) over 1 hour. Study participants will premedicate with oral dexamethasone 8
mg 1, 3, and 12 hours before the start of each docetaxel IV infusion. Oral prednisone 5 mg
will be administered twice daily.

Inclusion Criteria:

- Adenocarcinoma of the prostate

- Metastatic disease documented by bone, computed tomography (CT), or magnetic resonance
image (MRI) scan

- Surgical or medical castration with testosterone less than 50 ng/dL

- Prostate cancer progression documented by 1 of the following: PSA progression
according to Prostate Cancer Working Group 2 (PCWG2) criteria, radiographic
progression by modified Response Evaluation Criteria in Solid Tumors (RECIST) or bone
scan

- Absolute neutrophil count >1,500 cells/mm3

- Platelets >100,000/µl

- Hemoglobin >=10.0 g/dL

- Eastern Cooperative Group (ECOG) status score of <=2.

Exclusion Criteria:

- Elevated liver function tests (LFTs): Serum bilirubin >upper limit of normal (ULN),
alanine (ALT) or aspartate (AST) aminotransferase > 1.5 ULN concomitant with alkaline
phosphatase > 2.5 ULN

- Small cell carcinoma of the prostate

- Pulmonary or brain metastasis, liver metastasis is allowed if LFTs are not elevated

- Pre-existing neuropathy or severe fluid retention

- Prior cytotoxic chemotherapy for metastatic prostate cancer

- Prior therapy with other CYP17 inhibitor(s) or investigational agent(s) targeting the
androgen receptor for metastatic prostate cancer

- Treatment of primary tumor within 4 weeks of Day 1 Week 1 with surgery, radiation,
chemotherapy or immunotherapy

- Use of investigational drug within 4 weeks of Day 1 Week 1 or current enrollment in an
investigational drug or device study

- Prior ketoconazole for prostate cancer

- Recent history of ischemic heart disease, electrocardiogram (ECG) abnormalities, or
atrial fibrillation.