Phase II trial of thalidomide (T), bevacizumab (Bv), and docetaxel (Doc) in patients (pts) with metastatic castration-refractory prostate cancer (mCRPC)

Abstract

5000 Background: Angiogenesis has a vital role in progression of mCRPC. We hypothesized that combining the mechanistically different anti-angiogenic agents, T and Bv, with Doc would block multiple angiogenic pathways and lead to potent anti-tumor activity. Methods: Pts have progressive mCRPC and no prior chemotherapy for CRPC. Treatment regimen: Doc 75 mg/m2 + Bv 15 mg/kg day 1, q 21 days as a cycle (C), plus T 200 mg qhs and prednisone 10 mg qd. Enoxaparin for thrombosis prevention and pegfilgrastim after grade >3 neutropenia. PSA assay q C and staging studies at C 0, C 2, & then q 3 Cs. Results: All 60 pts have enrolled as planned, median age 66 [44- 79], Gleason score 8 [66% Gs 10∼8, 34% Gs 7∼5], on-study PSA 99 ng/ml [6.0–4,399], and pre-study PSA doubling time 1.6 months [0.3–18.2, 81 % < 3 months]. 2 pt had disease of no PSA activity. Median treatment Cs is 11 [2–46]. 51 pts (88%) had PSA declines of >50%, with median >50% PSA-duration 11 Cs [0∼45]. 5 pts had PSA declines <50%. 2 pts had no PSA decline. 41 pts (71%) had a >80% PSA decline. 32 pts with measurable disease were evaluable: 2 CR, 18 PR, 11 SD, & 1 PD, with 63 % ORR. The current estimated median PFS is 18.2 months. PSA-based concomitant rates of tumor regression and tumor growth (growth rate constant, g) are explored with a validated two-phase equation that shows a correlation of g with OS. The pretreatment g (10-1.885 in days-1) was reduced by > 10-fold to 10-3.155 on therapy, superior to prior Doc-containing therapies analyzed in this setting, with g values one third that of other regimens. Significant toxicities: febrile neutropenia (5/60), syncope (5/60), GI perforation or fistula (3/60), thrombosis (3/60), grade 3 bleeding (2/60). Conclusions: T and Bv with Doc are associated with high response rates, 88% in PSA and 63% in measurable disease, with expected toxicities. The regimen elicits a > 10-fold reduction in pre-treatment g values with projected better OS. The median estimated PFS of 18.2 months is very encouraging in this population of patients with unfavorable prognostic factors. These results suggest that combining T and Bv with Doc is worthy of further study for treatment of mCRPC. No significant financial relationships to disclose.