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

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