Preliminary evidence of efficacy and tolerance for weekly intravenous bortezomib plus mitoxantrone in patients with advanced androgen-independent prostate cancer (AIPCa)

Abstract

4567 Background: Bortezomib, a dipeptidyl boronic acid inhibitor of the 20S proteasome, has evidence of activity when given on a weekly schedule in patients with AIPCa. Of the cytotoxic agents approved for treatment of AIPCa, experimental models suggest anthracyclines exhibit consistently enhanced activity when given in combination with bortezomib. In an effort to build on these potential additive or synergistic effects, we developed a phase I study of weekly bortezomib (B) with weekly mitoxantrone (M) in patients (pts) with AIPCa. Methods: Twenty-one pts with progressive AIPCa received 63 cycles of B plus M given once weekly 4 weeks out of 5 using dose escalation with a continuous reassessment method. Three pts were treated at dose level 0 (B=1.4 mg/m2, M=2 mg/m2), and 18 at dose level 1 (B=1.4, M=3.0). Results: Median age was 63 yrs (range: 47–78). Nineteen pts received prior systemic chemotherapy (median # regimens: 2, range 0–7); 17 received prior taxane-based therapy. Therapy was well tolerated with only one G4 toxicity (unrelated basal cell cancer). G3 toxicities mainly included fatigue and neutropenia (4 each). Six pts required dose reduction: 4 due to G3 neutropenia (2 in cycle 1), and 2 due to Plt < 75,000. Only 1 pt had G2 neuropathy. Of the 18 pts completing at least 2 cycles and assessable for response, 3 (17%) pts with measurable disease achieved PR (both by PSA and in lymph nodes) and completed 5, 6, and 8 cycles of treatment. Two responders received prior chemotherapy; 1 progressed on non-taxane therapy, the other had 6 prior regimens of which 3 contained a taxane. Two additional heavily pre-treated pts (4 prior chemotherapy regimens each) achieved SD - the first pt had SD throughout all 8 cycles, while the other pt had a minor response in lymph nodes after 2 cycles, and continues on therapy. Conclusions: This schedule of bortezomib with mitoxantrone is well tolerated, and shows evidence of antitumor activity. Accrual to a cohort receiving bortezomib 1.4 mg/m2 and mitoxantrone 3.0 mg/m2 is ongoing. These observations may have broader implications in the development of proteasome inhibitors in combination with cytotoxic chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millenium Johnson & Johnson Pharmaceutical Research & Development