Androgen Deprivation Therapy and Vorinostat Followed by Radical Prostatectomy in Treating Patients With Localized Prostate Cancer

PRIMARY OBJECTIVES:

I. To determine the rate of pathologic complete response in patients with localized prostate
cancer treated with androgen depletion therapy (ADT) and oral vorinostat administered for a
minimum of 6 weeks and maximum of 8 weeks before radical prostatectomy.

SECONDARY OBJECTIVES:

I. To determine and evaluate pre- and post-treatment levels of prostate-specific antigen
(PSA), testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), and
dehydroepiandrosterone-dulfate (DHEA-S) in blood.

II. To determine and evaluate pre- and post-treatment levels of testosterone,
androstenedione, androstenediol, DHT, DHEA, and DHEA-S in prostate.

III. To determine and evaluate gene and protein expression analysis including androgen
receptor (AR) target genes, PSA and TMPRSS2 (transmembrane protease, serine 2), in
pre-treatment biopsy and post-treatment radical prostatectomy.

IV. To determine and evaluate exploratory gene microarray analysis. V. To determine and
evaluate the safety and tolerability of ADT in combination with vorinostat (SAHA) as assessed
by physical examinations, adverse events, and laboratory assessments.

OUTLINE:

Patients receive bicalutamide orally (PO) once daily (QD) for 1 month and leuprolide acetate
intramuscularly (IM) or goserelin acetate subcutaneously (SC) once a month until surgery.
Patients also receive vorinostat PO QD beginning on the first day of androgen depletion
therapy and continuing for up to 8 weeks or until the day of surgery. Patients then undergo
an open or laparoscopic radical prostatectomy. Patients with positive surgical margins
undergo immediate adjuvant external beam radiotherapy to the prostatic fossa, based on the
judgment of the treating physician.

After completion of study treatment, patients are followed every 3 months for up to 1 year.

Inclusion Criteria:

- Histologic documentation of prostatic adenocarcinoma in 3 or more biopsy cores, of
which at least 1 core demonstrates > 30% involvement with tumor; confirmation of
localized disease by magnetic resonance imaging (MRI) with endorectal probe if
available

- No evidence of distant disease on a:

- Computed tomography (CT) or MRI of the abdomen and pelvis

- Radionuclide bone scan (with plain film or MRI confirmation as clinically
indicated)

- Appropriate candidate for radical prostatectomy

- Adequate cardiac function (evidence of cardiac disease should be evaluated to
determine appropriateness of patient as a surgical candidate)

- Candidates may have a history of deep vein thrombosis, pulmonary embolism, and/or
cerebrovascular accident, or require concomitant systemic anticoagulation, if
otherwise deemed to be suitable for radical prostatectomy

- White blood cell (WBC) > 3000/uL

- Platelets > 150,000/uL

- Creatinine < 2 mg/dL

- Serum PSA < 100 ng/mL

- Bilirubin < 1.5 X ULN (institutional upper limits of normal)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2 X ULN

- Karnofsky performance status > 70%

- Willingness to undergo pretreatment transrectal ultrasound-guided prostate needle
biopsy (optional)

- Willingness to use adequate contraceptive methods during study therapy and for at
least 3 months after completion of therapy

- Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

- Evidence of small-cell, transitional-cell, or neuroendocrine pathologic features

- Prior hormonal therapy with (e.g. 5-alpha-reductase inhibitors, gonadotropin hormone
releasing analogs, steroids, megestrol acetate, or nonstudy-related antiandrogens),
chemotherapy, or herbal medications administered with the intent to treat the
patient's malignancy

- Patients on valproic acid (a histone-deacetylase inhibitor) to treat prostate
cancer are not eligible

- History of allergic reactions attributed to compounds of similar chemical or
biological composition to vorinostat

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situation that would compromise compliance
with study requirements

- Currently active secondary malignancy (as determined by the treating physician) other
than non-melanoma skin cancer