R-(-)-Gossypol and Androgen Ablation Therapy in Treating Patients With Newly Diagnosed Metastatic Prostate Cancer

PRIMARY OBJECTIVE:

I. To determine the percentage of patients with newly diagnosed metastatic prostate cancer who demonstrate undetectable prostate-specific antigen (PSA) (< 0.2 ng/mL) at 7 months when treated with R-(-)-gossypol (AT-101) and androgen ablation therapy.

SECONDARY OBJECTIVES:

I. To determine the safety of this regimen in these patients. II. To determine the percentage of patients with PSA >= 4.0 ng/mL, overall PSA < 4.0 ng/mL, and a PSA >= 0.2 ng/mL but < 4.0 ng/mL during the first 7 months of therapy.

OUTLINE:

Patients receive R-(-)-gossypol orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients may receive bicalutamide PO QD beginning 6 weeks before the initiation of R-(-)-gossypol and continuing after completion of treatment, at the discretion of the treating physician.

Inclusion criteria

• Histologically proven adenocarcinoma of the prostate with clinical stage D2 disease defined by soft tissue or bony metastasis.
• Patients must have elevated PSA ≥ 5 ng/ml within 12 weeks prior to registration. Androgen ablation therapy, which must include an LHRH agonist, will begin 6 weeks prior to initiation of AT101.
• Patients are allowed prior local therapy with radiation or surgery. Patients must not have received more than 12 months of androgen ablation therapy or antiandrogen therapy in the adjuvant/neoadjuvant setting and no prior androgen ablation therapy for metastatic disease, beyond the six week induction period prior to initiation of AT101. Patients with prior adjuvant/neoadjuvant androgen ablation therapy must have completed such therapy at least 12 months prior.
• Must be 18 years old or older.
• Life expectancy of greater than 6 months.
• ECOG performance status ≤ 2.
• Patients must have normal organ and marrow function as defined below:

• leukocytes ≥ 3,000/mcL
• absolute neutrophil count ≥ 1,500/mcL
• platelets ≥ 100,000/mcL
• total bilirubin within normal institutional limits
• AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal
• creatinine within normal institutional limits OR
• creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• There must be no plans to receive concomitant chemotherapy or radiation therapy during the study period. Baseline and on study PSA values must be obtained from the same reference laboratory.
• The effects of AT101 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason men and/or their partners must agree to use adequate contraception, (including hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation.

Exclusion criteria

• Patients who have had radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Patients may not be receiving any other investigational agents.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AT101 or other agents used in the study.
• Patients with bilateral orchiectomy are not eligible.
• Patients presenting with acute cord compression are not eligible.
• History of bowel obstruction or GI dismotility disorder.
• 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 situations that would limit compliance with study requirements.
• Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain AT-101 tablets.
• Requirement for routine use of hematopoietic growth factors (including granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, or interleukin-11) or platelet transfusions to maintain absolute neutrophil counts or platelets counts above the required thresholds for study entry.
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AT-101.