Angiogenesis inhibition in metastatic hormone refractory prostate cancer (HRPC): A randomized phase II trial of two doses of the matrix metalloproteinase inhibitor (MMPI) BMS-275291

Abstract

4647 Background: BMS-275291 is a selective MMPI that does not inhibit sheddases implicated in the dose-limiting arthritis of older MMPIs. We conducted a randomized phase II trial of 2 doses of BMS-275291 (1200 vs. 2400 mg) in HRPC patients (pts) with bone metastasis to probe for a dose-response relationship and assess differential toxicities. Methods: Primary endpoint was 4-month progression-free survival (PFS): 68 pts were needed to detect PFS > 50% versus a null hypothesis of PFS 60%, and no more than 1 prior chemotherapy regimen. Pts were randomized to 1200 mg po QD (Arm A) vs. 1200 po BID (Arm B). Results: Rapid multi-center accrual resulted in 80 pts randomized w/in 14 months (mos): Arm A –39, Arm B –41. Pt characteristics: median age=70 yrs; Gleason's 7/unspecified = 0/34/33/13; KPS > 80% = 67 pts; prior chemo = 25%. Attributable grade 3–4 toxicities were 15% in Arm A, 24% in Arm B. There were no responders. At 2 mos, 22 progressed on Arm A vs. 29 on B. PFS at 4 mos in Arms A and B were 25% and 8%, respectively. Median overall survival was not reached in Arm A, 12 mos in Arm B. PSA slope was compared in 54 pts with at least 2 pre-treatment, on-study, and post-treatment PSA values using a paired t-test. Mean pre/post change in PSA slopes was 0.0018 (p=0.3), equivalent to an increase in PSA doubling time from 70 to 86 days. Evaluation of bone metabolism markers from serial plasma/urine samples is ongoing. Conclusions: 1) BMS-275291 was well tolerated in HRPC pts and had no dose limiting arthritis. 2) Toxicities differed modestly according to dose-schedule employed. 3) PFS and response were similar between the arms, with a trend towards decreasing PSA slope pre- vs. on-treatment. 4) In view of its presumed cytostatic mechanism of action, further studies to define the effect of BMS-275291 in earlier stage disease could be performed at either dose studied here. (NOI CM17101, CM17102, ACS-CRTG 19701-CCE) No significant financial relationships to disclose.