RATIONALE: Drugs used in chemotherapy, such as mitoxantrone, work in different ways to stop tumor cells from dividing so they stop growing or die. Bortezomib may stop the growth of tumor cells by blocking the enzymes necessary for their growth and may also make tumor cells more sensitive to chemotherapy. Combining bortezomib with mitoxantrone may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib and mitoxantrone in treating patients with advanced or metastatic androgen-independent prostate cancer.

Condition	Treatment or Intervention	Phase
recurrent prostate cancer stage III prostate cancer stage IV prostate cancer	Drug: bortezomib  Drug: mitoxantrone  Procedure: chemosensitization/potentiation  Procedure: chemotherapy  Procedure: enzyme inhibitor therapy	Phase I

Further Study Details: 

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 3 patients receive escalating doses of bortezomib and mitoxantrone until the maximum tolerated dose (MTD) is determined. 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 within 10.5 months.

Genders Eligible for Study:  Both

Criteria

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

Texas
      MD Anderson Cancer Center at University of Texas, Houston,  Texas,  77030-4009,  United States; Recruiting

Study chairs or principal investigators

Arlene Siefker-Radtke, MD,  Study Chair,  M.D. Anderson Cancer Center   
Christopher Logothetis, MD,  M.D. Anderson Cancer Center   

Study ID Numbers:  CDR0000355822; MDA-ID-02227; MILLENNIUM-MDA-ID-02227; NCT00082680
Record last reviewed:  April 2004
Last Updated:  March 15, 2005
Record first received:  May 14, 2004
ClinicalTrials.gov Identifier:  NCT00082680
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08