Phase I Study of Weekly Intravenous PS-341 (Bortezomib) Plus Mitoxantrone

Inclusion Criteria:

1. Patient has given voluntary written informed consent before performance of any study-related procedure not part of standard medical care.
2. Patient has histologically-confirmed advanced and/or metastatic AI-PCa requiring anti-neoplastic treatment. Patients should continue on LHRH analog therapy throughout the study period, if this is their mode of androgen suppression therapy. Patients should have discontinued anti-androgen therapy for \>/= than 4 weeks (for flutamide) or \>/= 6 weeks (for bicalutamide and nilutamide).
3. Patient has progressive measurable or evaluable disease, defined as meeting at least one of the three criteria, described in protocol section 4.1.
4. Zubrod performance status of \</= 2 (Appendix B).
5. Resting Left Ventricular Ejection Fraction (LEVF) \>/= 50%.
6. Patient has all of the following pretreatment laboratory data within 14 days (except for serum testosterone which may be done within 28 days prior to registration) before the first study drug dose: Absolute neutrophil count (ANC) \>/= 1,500/mm\^3. Platelets \>/= 100,000/mm\^3. Hemoglobin \>8.0 g/dL. Total bilirubin \</=1.5 x the upper limit of normal (ULN). ALT or AST \</= 2.5 x the ULN, or, if the patient has liver metastases, \</= 5 x the ULN. Creatinine \</= 2 mg/dL. Serum testosterone \</= 50 ng/mL.

Exclusion Criteria:

1. Patient has received chemotherapy (including thalidomide or ketoconazole) within four weeks, nitrosoureas within six weeks, or antibody therapy within eight weeks of enrollment.
2. Patient has received radiation therapy or Samarium-153 within four weeks of enrollment, or Strontium-89 within 12 weeks of enrollment.
3. Patient has not recovered from all serious toxic effects of previous chemotherapy or radiation or antibody therapy.
4. Patient received treatment with flutamide within four weeks of enrollment or nilutamide or bicalutamide within six weeks of enrollment.
5. Patient has had any major surgery within four weeks of enrollment.
6. Patient has a history of allergic reactions to anti-diarrheal medications or anti-emetics suggested to be administered in conjunction with study drug (see Section 5.1.4.1).
7. Patient has a history of severe hypersensitivity reaction to mitoxantrone or other agents formulated with polysorbate 80.
8. Patients with significant atherosclerotic disease, as defined by: a) myocardial infarction within six months of enrollment, uncontrolled / unstable angina pectoris or electrocardiographic evidence of acute ischemia b) clinically significant ventricular arrhythmias, c) symptomatic congestive heart failure d) significant conduction abnormalities: 2nd or 3rd degree AV blocks, bifascicular block (defined as Left Anterior Hemiblock in the presence of Right Bundle Branch Block), e) claudication limiting activity and f) history of cerebrovascular events within the last year (including TIA)
9. Patients who have received \> equivalent to 180 mg/m\^2 of Doxorubicin cumulative dose.
10. Patients with diabetes mellitus requiring insulin, or those that have required pharmacologic intervention for diabetes mellitus for greater than 5 years
11. Patient has uncontrolled brain metastases or central nervous system disease.
12. Patient has \>/= Grade 2 peripheral neuropathy (per NCI CTC v.2).
13. Patient has an uncontrolled intercurrent illness (e.g., active infection).
14. Patient has another serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the patient's ability to provide informed consent or with the completion of treatment according to this protocol.