Treating Patients With Metastatic Prostate Cancer Not Responding to Hormone and Chemotherapy

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and dose-limiting toxicities of the combination of ixabepilone, mitoxantrone hydrochloride, and prednisone in patients with hormone-refractory metastatic prostate cancer that progressed during or after taxane-based chemotherapy. (Phase I) II. Assess the efficacy, as measured by reduction in prostate-specific antigen, of this regimen in these patients. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate the overall safety of this regimen as second-line chemotherapy in these patients.

II. Evaluate the objective response rate in patients treated with this regimen.

OUTLINE: This is a multicenter, phase I, open label, dose-escalation study of mitoxantrone hydrochloride and ixabepilone followed by a phase II study.

PHASE I: Patients receive mitoxantrone hydrochloride intravenously (IV) over 30 minutes and ixabepilone IV over 3 hours on day 1 and oral prednisone twice daily on days 1-21. Treatment repeats every 21 days for ≥ 3 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of mitoxantrone hydrochloride and ixabepilone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

PHASE II: Patients receive mitoxantrone hydrochloride and ixabepilone at the MTD determined in phase I and prednisone as in phase I.

After completion of study treatment, patients are followed every 3 months.

Inclusion criteria

• Histologically confirmed adenocarcinoma of the prostate
• Progressive metastatic disease (i.e., positive bone scan or measurable disease) despite castrate levels of testosterone (either from orchiectomy or luteinizing hormone-releasing hormone [LHRH] agonist therapy)

• Progressive disease after discontinuing hormonal therapy
• Progressive disease is based on any of the following*:

• Transaxial imaging
• Rise in prostate-specific antigen (PSA)
• Radionuclide bone scan (must show new metastatic lesions)
• Nonmeasurable or measurable disease

• For measurable disease, progression is defined by RECIST criteria
• Positive bone scan and elevated PSA required for nonmeasurable disease

• PSA evidence of progressive prostate cancer during or after first-line chemotherapy consists of a PSA level ≥ 2 ng/mL that has risen on ≥ 2 successive occasions ≥ 1 week apart
• Received ≥ 3 prior courses of paclitaxel- or docetaxel-based therapy, with disease progression documented during therapy or after cessation of therapy

• No more than 1 prior chemotherapy regimen
• Re-treatment with the same taxane-based regimen allowed
• Changes in prior chemotherapy regimen (addition of other agents) for disease progression are considered 2 chemotherapy regimens, and are not allowed
• PSA ≥ 2 ng/mL
• Testosterone < 50 ng/dL

• Patients must continue primary androgen deprivation with LHRH analogue if they have not undergone orchiectomy
• No known active brain metastases
• ECOG performance status 0-2
• Life expectancy ≥ 12 weeks
• Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance > 40 mL/min
• ALT and AST < 2.5 times ULN
• Granulocyte count ≥ 2,000/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin < 1.5 times ULN
• Ejection fraction normal by MUGA scan or echocardiogram
• No significant cardiovascular disease, including any of the following:

• Congestive heart failure (New York Heart Association class III-IV heart disease)
• Active angina pectoris
• Myocardial infarction within the past 6 months
• No serious infections or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by study therapy
• No psychiatric illness or social situation that would preclude study compliance
• No pre-existing motor or sensory peripheral neuropathy > grade 1
• No known prior severe hypersensitivity reactions to agents containing Cremophor® EL
• No "currently active" second malignancy other than nonmelanoma skin cancer

• Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered to be at < 30% risk of relapse
• Fertile patients must use effective contraception prior to, during, and for 3 months after completion of study treatment
• See Disease Characteristics
• No prior mitoxantrone hydrochloride, ixabepilone, or other epothilones
• At least 4 weeks since prior hormonal therapy (i.e., any dose of megestrol, finasteride, or any herbal product known to decrease PSA levels [e.g., saw palmetto or PC-SPES]) other than LHRH agonist or a stable dose of corticosteroids from a prior chemotherapy regimen
• More than 4 weeks since other prior systemic therapies for prostate cancer
• At least 4 weeks since prior radiation therapy
• More than 8 weeks since prior radiopharmaceuticals (e.g., strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium)
• No concurrent moderate to strong CYP3A4 inhibitors
• No concurrent prophylactic colony-stimulating factors
• No concurrent radiotherapy