S1216, Phase III ADT+TAK-700 vs. ADT+Bicalutamide for Metastatic Prostate Cancer

Inclusion Criteria:

- Clinical diagnosis of metastatic prostate cancer.

- Serum testosterone within institutional limits of normal.

- PSA ≥ 2 ng/mL within 90 days prior to initiation of androgen deprivation. therapy (for
early induction) or prior to registration (for late induction).

- DEXA scan within 2 years prior to registration.

- ECG within 42 days prior to registration and QTc interval ≤ 460 msec.

- LVEF within 42 days prior to registration and within institutional limits of normal.

- Adequate hepatic function as evidenced by bilirubin ≤ 2 x institutional upper limit of
normal (ULN), SGOT (AST) and SGPT (ALT) ≤ 3 x institutional ULN, or ≤ 5 x
institutional ULN if liver metastases are present.

- Adequate renal function as evidenced by calculated creatinine clearance ≥ 40 mL/min.

- Adequate hematologic function as evidenced by leukocytes ≥ 3,000/mcL, absolute
neutrophil count (ANC) ≥ 1,500/mcL, hemoglobin ≥ 9 g/dL, and platelets ≥ 100,000/mcL.

- Zubrod performance status of 0 - 2. Zubrod performance status 3 will be allowed if
from bone pain only.

- ≥ 18 years of age.

- Men of reproduction potential and those who are surgically sterilized (i.e.,
postvasectomy) must agree to practice effective barrier contraception or agree to
abstain from intercourse while receiving treatment on this study and for at least 4
months after protocol treatment ends.

Exclusion Criteria:

- Known brain metastases.

- No more than 36 months of prior neoadjuvant and/or adjuvant hormonal therapy.

- ≥ 6 months since completion of androgen deprivation therapy.

- Prior or concurrent therapy with ketoconazole, aminoglutethimide or abiraterone
acetate, or enzalutamide (MDV3100). Concurrent megestrol for hot flashes is allowed.

- Prior chemotherapy for treatment of metastatic prostate cancer. Prior chemotherapy in
the neoadjuvant or adjuvant setting is allowed.

- ≥ 2 years since completion of chemotherapy in the neoadjuvant or adjuvant setting.

- Concurrent use of experimental therapy is not allowed.

- ≥ 30 days since prior medical castration for metastatic prostate cancer.

- If method of castration is a LHRH agonist, the patient must be willing to continue the
use of LHRH and add bicalutamide or TAK-700 during protocol treatment.

- If the patient was on an antiandrogen (e.g. bicalutamide, flutamide), the patient must
be willing to switch over to bicalutamide or TAK-700 (according to randomization).

- Prior bilateral orchiectomy.

- Concurrent use of LHRH antagonists (e.g. Degarelix)

- Grade III/IV cardiac disease (as defined by the NYHA Criteria), thromboembolic event,
unstable angina pectoris, myocardial infarction within 6 months, or serious
uncontrolled cardiac arrhythmia.

- Uncontrolled hypertension (defined as blood pressure > 160 mmHg systolic and > 90 mmHg
diastolic at 2 separate measurements no more than 60 minutes apart during the
Screening visit) despite appropriate medical therapy.

- Known human immunodeficiency virus (HIV)infection, active chronic hepatitis B or C,
life-threatening illness unrelated to cancer, or any serious medical or psychiatric
illness that could, in the investigator's opinion, potentially interfere with
participation in this study.

- History of primary and secondary adrenal insufficiency.

- Hypersensitivity to TAK-700, to TAK-700 metabolites, to bicalutamide, or to LHRH
agonists.

- Gastrointestinal (GI) disease or GI procedure that could interfere with the GI
absorption or tolerance of TAK-700, including difficulty swallowing oral medications.

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, adequately treated Stage I or II cancer from
which the patient is currently in complete remission, or any other cancer from which
the patient has been disease-free for 5 years.