OBJECTIVES:

Primary

• Determine the dose-limiting toxicity and maximum tolerated dose (MTD) of bortezomib and mitoxantrone in patients with advanced or metastatic androgen-independent prostate cancer.

Secondary

• Determine the degree of proteasome inhibition in peripheral blood of patients treated with this regimen.
• Correlate the effect of this regimen on prostate-specific antigen (PSA) levels with the degree of proteasomal inhibition in the blood of patients with baseline PSA levels ≥ 5 ng/mL who are treated near the MTD.
• Determine the effect of this regimen on selected parameters of clinical benefit (i.e., performance status, tumor-related symptoms, and measurable disease response) in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive bortezomib IV and mitoxantrone IV on days 1, 8, 15, and 22. Treatment repeats every 35 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of patients receive escalating doses of bortezomib and mitoxantrone until the maximum tolerated dose (MTD) is determined using a continuous reassessment method for dose escalation. The MTD is defined as the dose level having a mean posterior dose-limiting toxicity probability closest to 25%.

Patients are followed at 3 weeks.

PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed androgen-independent prostate cancer

  • Advanced or metastatic disease
• Requires antineoplastic therapy
• Progressive measurable or evaluable disease
• Testosterone ≤ 50 ng/dL
• No uncontrolled brain metastases
• No CNS disease

PATIENT CHARACTERISTICS:

Age

• Not specified

Performance status

• Zubrod 0-2

Life expectancy

• At least 3 months

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Hemoglobin > 8.0 g/dL
• Platelet count ≥ 100,000/mm^3

Hepatic

• ALT or AST ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases are present)
• Bilirubin ≤ 1.5 times ULN

Renal

• Creatinine ≤ 2 mg/dL

Cardiovascular

• LVEF ≥ 50% at rest

• None of the following significant atherosclerotic diseases:

  • Myocardial infarction within the past 6 months
  • Uncontrolled or unstable angina pectoris
  • Acute ischemia by ECG
  • Clinically significant ventricular arrhythmias
  • Symptomatic congestive heart failure

  • Any of the following significant conduction abnormalities:

    • Second- or third-degree atrioventricular block
    • Bifascicular block (defined as left anterior hemiblock in the presence of right bundle branch block)
  • Claudication limiting activity
  • Cerebrovascular events with the past year (including transient ischemic attack)

Other

• No prior allergic reaction to antidiarrheal medications or antiemetics
• No prior severe hypersensitivity reaction to mitoxantrone or other agents formulated with polysorbate 80
• No active infection
• No other concurrent uncontrolled illness
• No diabetes mellitus requiring insulin OR that required pharmacologic intervention for more than 5 years
• No peripheral neuropathy ≥ grade 2
• No other serious medical or psychiatric illness that would preclude study compliance or treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 8 weeks since prior antibody therapy and recovered

Chemotherapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) and recovered
• No prior cumulative doxorubicin dose ≥ 180 mg/m^2

Endocrine therapy

• At least 4 weeks since prior flutamide (6 weeks for bicalutamide or nilutamide)
• Patients receiving luteinizing hormone-releasing hormone analog therapy for androgen suppression should continue this therapy throughout study participation

Radiotherapy

• More than 4 weeks since prior radiotherapy and recovered
• More than 4 weeks since prior samarium Sm 153 lexidronam pentasodium
• More than 12 weeks since prior strontium chloride Sr 89

Surgery

• More than 4 weeks since prior major surgery