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Background: Angiogenesis appears to play critical role in the progression of mCRPC. Previously we have shown anti-tumor activity in mCRPC with the combination of D, thalidomide (T), A and P (Ning JCO 2010). We hypothesized that combining R, an analogue of T, with A, D and P would have a more favorable toxicity profile and similar anti-tumor activity.
Methods: All pts had chemotherapy-naïve progressive mCRPC. 6 pts were treated with R at 15 and 20 mg prior to doses at 25 mg. Treatment is 75 mg/m
2
D, 15 mg/kg A every 21 days as one cycle (C), plus 25 mg R for 14 days with daily 10 mg P and enoxaparin. After grade 3 neutropenia was seen in > 80% of pts in all cohorts, the protocol was amended to include prophylactic pegfilgrastim. PSA is tested each C with imaging after C2 and then every 3C. Dental exams with mandible CT's are at baseline, after C5, and then every 6C or earlier if needed.
Results: 28 of a planned 51 pts have been enrolled. Pt characteristics include: median age 65.5 [51-78], Gleason score 8 [67.9% 8-10, 32.1% 6-7], on-study PSA 94.3 ng/mL [9.2-3520], and pre-study PSA doubling time 1.43 months [0.52-4.07]. Median C number was 8 [1-21]. 2/28 pts were off study due to clinical or radiographic progression. 26 pts remain on study. 22/24 (91.7%) and 20/24 (83.3%) pts who have completed ≥ 4C had PSA- decline of ≥ 50% and ≥ 75%, respectively. 14 pts with measurable disease were evaluable with 2 CRs (1 unconfirmed), 9 PRs (2 unconfirmed), and 3 SDs (a 78.6% overall RR). Grade ≥ 3 toxicities include neutropenia (16/28), anemia (6/28), thrombocytopenia (3/28), hypertension (1/28), and infection (2/28). 1/28 pts had febrile neutropenia. 8/28 pts (28.6%) developed grade 2 osteonecrosis of the jaw (ONJ), defined as bone death on dental exam, higher than 18.3% as reported by Ning. 5/8 had concomitant and 2/8 pts had history of bisphosphonate use.
Conclusions: Combined therapy with anti-angiogenic agents R and A, plus D and P is associated with high response rates, 91.7% in PSA and 78.6% in measurable disease in mCRPC pts, with manageable toxicities. Further study is underway to characterize the activity and to explore the high incidence of ONJ, including the possibility of ascertainment bias.
No significant financial relationships to disclose.