Aims: This study is designed to explore the molecular modulatory effects of sunitinib in an effort to determine a safe and effective dose when given in a neoadjuvant setting before radical prostatectomy.

Methods: The study will evaluate the biologic effects in 25 patients of two dose levels and three treatment durations administered before prostatectomy. The tumor will then be resected via radical prostatectomy 24 hours after the last dose of sunitinib, and subjects will remain in clinical follow-up for 1 year. Pretreatment tumor biopsies used to establish diagnosis and post-treatment surgical specimens will be assayed for a host of biomarker expression. Sunitinib (SU011248) is an orally administered, small molecule that inhibits the tyrosine kinase activities of the growth factors for vascular endothelial growth factor and platelet-derived growth factor and blocks signaling through KIT. Clinically, sunitinib has good oral bioavailability, linear pharmacokinetics, and a prolonged half-life (~ 40 hours). Repeated dosing over a range of 25 mg to 100 mg daily has been performed, either on a repeated 4-week cycle comprising daily treatment for 2 weeks followed by a 2-week rest period or a repeated 6-week cycle comprising daily treatment for 4 weeks followed by a 2-week rest period. Sunitinib is especially suited for neoadjuvant therapy and potential downstaging of prostate tumors because of its demonstrated capability of shrinking and downsizing rather large kidney tumors, in which it has demonstrated 40% response rates and up to 90% shrinkage of target lesions in these difficult solid tumors. No other targeted drug has shown similar activity. This study will be a phase I, open-label, singlecenter, multiple-dose, dose-escalation clinical study of sunitinib in subjects with high-risk prostate cancer who have elected to undergo radical prostatectomy with the following objectives. The primary objective will be to evaluate the effects of sunitinib by histologic examination of prostate tumors after radical prostatectomy (ie, apoptosis, inflammatory infiltrate, etc.) and to determine the safety and maximum tolerable dose of sunitinib when administered as an neoadjuvant treatment for up to 4 weeks in patients with prostate cancer before radical prostatectomy. Secondary objectives will include the evaluation of the effects of sunitinib on tumoral phospho vascular endothelial growth factor/platelet-derived growth factor, receptor tyrosine kinase pathways, microvessel density, antiangiogenic activities, other known biologic targets of sunitinib activity, and on serum PSA levels.