OBJECTIVES:

• Determine the maximum tolerated dose of ixabepilone combined with estramustine in patients with progressive androgen-independent adenocarcinoma of the prostate. (Phase I)
• Compare the safety and efficacy of ixabepilone with or without estramustine in this patient population. (Phase II)
• Correlate the clinical outcomes with reverse transcriptase-polymerase chain reaction-based assay for prostate-specific antigen mRNA in patients treated with these regimens.

OUTLINE: This is a dose-escalation study of ixabepilone (phase I) followed by a randomized, multicenter study (phase II).

• Phase I: Patients receive ixabepilone IV over 3 hours on day 2 and oral estramustine 3 times daily on days 1-5. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of ixabepilone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive ixabepilone IV over 3 hours at the MTD on day 2 and estramustine as in phase I.
  • Arm II: Patients receive ixabepilone IV over 3 hours at the MTD on day 1. Treatment in both arms repeats as in phase I.

Patients are followed every 12 weeks until disease progression.

PROJECTED ACCRUAL: A total of 3-12 patients will be accrued for phase I of this study and a total of 44-92 patients (22-46 per treatment arm) will be accrued for phase II of this study within 12-18 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the prostate

• Must have disease progression meeting 1 of the following criteria:

  • Rising prostate-specific antigen (PSA) on at least 3 consecutive measurements taken more than 1 week apart
  • Measurable disease, defined as new or progressive soft tissue masses on CT scan or MRI
  • New metastatic lesions by radionuclide bone scan
• The most recent PSA must be at least 4 ng/mL if no measurable disease is present
• Ineligible if sole manifestation of progressive disease is an increase in disease-related symptoms
• Serum testosterone no greater than 50 ng/mL

• One of the following therapies for maintenance of castrate status required:

  • Must continue on gonadotropin-releasing hormone analogs (e.g., leuprolide or goserelin) to maintain castrate levels of serum testosterone

    • Developed disease progression after discontinuation of the antiandrogen that was part of the first-line hormonal therapy
  • Prior surgical orchiectomy
• Developed disease progression after discontinuation of megestrol
• No known brain metastases

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 70-100%

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• No history of bleeding disorder that would preclude anticoagulation with warfarin

Hepatic:

• Bilirubin normal
• AST/ALT no greater than 2.5 times upper limit of normal (ULN)
• PT/PTT normal (unless anticoagulated for other reasons [e.g., atrial fibrillation])

Renal:

• Creatinine no greater than 1.5 times ULN

Cardiovascular:

• No significant cardiovascular disease
• No symptomatic congestive heart failure
• No New York Heart Association class III or IV heart disease
• No active unstable angina pectoris
• No cardiac arrhythmia
• No myocardial infarction within the past 6 months
• No history of hemorrhagic or thrombotic cerebrovascular accident or deep venous thrombosis within the past 6 months

Pulmonary:

• No pulmonary embolism within the past 6 months

Other:

• Fertile patients must use effective contraception
• No history of allergic reactions to compounds of similar chemical or biological composition to the epothilones
• No history of recent gastrointestinal bleeding that would preclude anticoagulation with warfarin

• No other concurrent active malignancy except nonmelanomatous skin cancer

  • Disease not considered currently active if completely treated with less than a 30% risk for relapse
• No other concurrent uncontrolled illness
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent routine filgrastim (G-CSF) or sargramostim (GM-CSF) except for neutropenic fever
• No concurrent immunotherapy

Chemotherapy:

• No prior chemotherapy
• No other concurrent chemotherapy

Endocrine therapy:

• See Disease Characteristics

Radiotherapy:

• No prior palliative radiotherapy to more than 25% of bone marrow
• No prior radioisotope therapy with strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium
• No concurrent therapeutic radiotherapy
• Concurrent focal radiotherapy for palliation of bone disease-related symptoms allowed at the investigator's discretion

Surgery:

• See Disease Characteristics
• At least 4 weeks since prior major surgery

Other:

• No other concurrent anticancer investigational or commercial agents or therapies
• No concurrent herbal, alternative, or food supplements (e.g., PC-SPES, saw palmetto, or St. John's Wort)
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No initiation of bisphosphonates immediately before or during study
• Concurrent bisphosphonates allowed if developed disease progression while on stable doses
• Concurrent daily multivitamin allowed