Abstract 741: Sunitinib plus hormone ablation and radiation therapy for patients with high-risk localized prostate cancer: Results from a multi-institutional phase I study

Abstract

Abstract Background: Novel strategies are needed to improve the long-term outcomes of patients (pts) with high-risk prostate cancer treated with hormonal ablation and external beam radiation therapy (XRT). Preclinical data suggest that angiogenesis inhibitors normalize vasculature, reduce hypoxia, and improve the therapeutic index of XRT. To assess the feasibility of combined VEGFR/PDGFR inhibition in combination with XRT, a Phase I study with sunitinib was initiated. Methods: Seventeen men with adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or PSA > 20ng/ml received initial hormonal ablation (leuprolide 22.5mg every 12 weeks + oral bicalutamide 50mg daily) for 4-8 weeks prior to oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks post XRT (prostate and proximal seminal vesicles received 75.6 Gy in 42 fractions with at least 50 Gy for the distal seminal vesicles). A 3+3 sequential dose-escalation design was employed to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose (MTD) of sunitinib. Results: The first 4 pts enrolled on 37.5 mg experienced a DLT during lead-in. *With 2 pts unexpectedly experiencing Grade 3 neutropenia and a third experiencing Grade 3 thrombocytopenia, a drug-interaction with bicalutamide was suspected. The protocol was revised to replace these pts and omit concurrent bicalutamide. Of these first 4 pts, 3 were dose reduced to 25 mg and successfully completed full treatment, while 1 pt withdrew. Of the next 3 pts subsequently enrolled at 37.5 mg, 2 of 3 on concurrent therapy have experienced DLTs (G3 diarrhea with concomitant sunitinib-induced thyrotoxicosis; G3 proctitis). Conclusions: Using a daily dosing regimen and a lead-in phase, the MTD of concurrent sunitinib, hormonal ablation and XRT was 37.5mg daily. The recommended Phase 2 dose of sunitinib for further study is 25mg daily. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 741. doi:1538-7445.AM2012-741