An Endocrinologically and Pharmacologically Directed Trial of Ketoconazole and Corticosteroids in Castration Resistant Prostate Cancer

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the prostate.

- Testosterone < 50 ng/dL. Patients must continue primary androgen deprivation with an
LHRH analogue if they have not undergone orchiectomy.

- Progressive non-metastatic or metastatic disease after androgen deprivation. Patients
must have EITHER:

1. Progression as defined by RECIST criteria. OR

2. Progressive PSA documented within 4 weeks of enrollment. PSA evidence for
progressive prostate cancer consists of a PSA level of at least 5 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 first documented rising PSA value, then
an additional test for rising PSA will be required to document progression.

- Patients who are receiving an antiandrogen as part of primary androgen ablation must
demonstrate disease progression following discontinuation of antiandrogen.

1. 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.

2. For patients receiving flutamide, at least one of the PSA values must be
obtained 4 weeks or more after flutamide discontinuation.

3. For patients receiving bicalutamide (Casodex) or nilutamide, at least one of the
PSA values must be obtained 6 weeks or more after antiandrogen discontinuation.

- Karnofsky Performance Status ≥ 60%.

- Patients receiving any other hormonal therapy, including any dose of megestrol
acetate (Megace), Proscar (finasteride), any herbal product known to decrease PSA
levels (e.g., Saw Palmetto and PC-SPES), or any systemic corticosteroid must
discontinue the agent for at least 4 weeks prior to enrollment.

- Patients on stable doses of bisphosphonates may continue on this medication; further,
patients may initiate bisphosphonate therapy at the time of ketoconazole initiation.

- Prior radiation therapy completed ≥ 4 weeks prior to enrollment.

- Liver function tests (ALT, AST, and Bilirubin) must be within normal limits.

- ANC >1500/µl, Platelet count > 100,00/µl, Creatinine <1.5 x upper limit of normal
(ULN), Hemoglobin > 8 mg/dl.

Exclusion Criteria:

- Prior chemotherapy for prostate cancer is not allowed with the exception of cases in
which chemotherapy has been administered in a neoadjuvant or adjuvant fashion AND >1
year has elapsed since the administration of this therapy.

- No prior ketoconazole, abiraterone, aminoglutethimide or corticosteroids for
treatment of progressive prostate cancer.

- No supplements or complementary medicines/botanicals are permitted while on protocol
therapy, except for any combination of the following: (conventional multivitamin
supplements, selenium, lycopene, soy supplements) No prior radiopharmaceuticals
(strontium, samarium) within 8 weeks prior to enrollment.

- No "currently active" second malignancy, other than non-melanoma skin cancer.

- No serious intercurrent infections or nonmalignant medical illnesses that are
uncontrolled.

- No psychiatric illnesses/social situations that would limit compliance

- No active or uncontrolled autoimmune disease.

- No adrenal insufficiency as demonstrated by a baseline ACTH stimulation test
demonstrating a peak cortisol >18 µg/dL.