Zoledronate and BMS-275291 in Treating Patients With Prostate Cancer

PRIMARY OBJECTIVES:

I. To evaluate the confirmed response rate of hormone refractory prostate cancer patients treated with Zometa with BMS-275291.

SECONDARY OBJECTIVES:

I. To evaluate the toxicity profile associated with this treatment in this patient population.

II. To evaluate the overall and progression-free survival associated with this treatment regimen.

III. To explore changes markers for bone turnover, fPYR, fDPYR, and serum samples for cross-linked N-telopeptides from baseline.

IV. To assess changes in bone tumor metabolism after treatment using PET scans. V. To assess changes in MMP-1, MMP-9, VEGF and bFGF from baseline after treatment.

OUTLINE: This is an open-label, multicenter study. Patients are stratified according to prior chemotherapy (yes vs no) and participating center.

ARM I: Patients receive zoledronate IV over at least 15 minutes on day 1 and oral BMS-275291 daily on days 1-28.

ARM II (CLOSED TO ACCRUAL AS OF 10/10/2003): Patients receive zoledronate as in Arm I.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months until disease progression and then every 6 months for up to 2 years.

Inclusion criteria

• Histologically or cytologically confirmed (adeno)carcinoma of the prostate refractory to hormone therapy
• Metastatic bone disease, as documented by bone scan and confirmed by x-rays, CT scan or MRI scan

• Note: Patients may also have measurable disease in the lymph nodes (retroperitoneal, pelvic or inguinal only), prostate and /or prostatic bed; measurable disease is defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm =< 21 days prior to registration
• PSA progression defined as two consecutive increases in PSA value over the previous reference value; the first increase of PSA should occur no earlier than one (1) week after the reference measurement; all patients need to demonstrate continued PSA elevation with an increasing PSA four weeks after the required cessation of their antiandrogen treatment; the required cessation period is 4 weeks for flutamide, nilutamide, and Megace-based treatment, and 8 weeks for bicalutamide-based treatment
• One of the following:

• Continuing primary androgen suppression (LHRH agonist)
• Orchiectomy
• WBC >= 2000/mm^3
• Absolute neutrophil count (ANC) >= 1500/mm^3
• PLT >= 100,000/mm^3
• Hgb >= 9.0 g/dL
• Total bilirubin =< institutional upper normal limits (UNL)
• AST =< 1.5 x UNL
• Serum creatinine =< 1.5 x UNL
• PSA >= 5 ng/mL
• Serum testosterone < 50 ng/dL =< 3 months prior to registration
• Estimated life expectancy of >= 6 months
• ECOG Performance Status (PS) 0, 1, or 2
• Capable of understanding the investigational nature, potential risks and benefits of the study and able to provide valid informed consent
• If sexually active, willing to use an accepted and effective method of contraception consistently for the duration of study participation

Exclusion criteria

• Any of the following:

• > 2 prior chemotherapy regimen
• > 2 non-hormonal treatments for metastatic disease (including biologics, gene therapy, angiogenesis inhibitors, etc., but excluding external radiotherapy)
• Prior therapy with a matrix metalloproteinase inhibitor (MMPI)
• Immunotherapy =< 4 weeks prior to study entry
• Biologic therapy =< 4 weeks prior to study entry
• Radiation therapy =< 4 weeks prior to study entry
• Concomitant hormonal treatment (except LHRH)
• Prior use of systemic radiopharmaceuticals such as samarium and strontium
• PC-Spes =< 4 weeks prior to study entry
• Failure to fully recover from adverse effects of prior therapies regardless of interval since last treatment
• Other concurrent chemotherapy, immunotherapy, or radiotherapy directed at the cancer
• Other therapy or supportive care that is considered investigational
• Known CNS metastases
• Known visceral metastases (pulmonary, liver, kidney, splenic lesions); patients with retroperitoneal, pelvic or inguinal lymph node metastases and/or disease in the prostate (or prostatic bed) will not be excluded
• Uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris, cardiac arrhythmia
• Psychiatric illness/social situations that would limit compliance with study requirements
• HIV-positive patients receiving combination anti-retroviral therapy
• Prior malignancy except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas, or other cancer from which the patient has been disease free for >= 5 years