5011 Background: We conducted a Phase I trial of S and B to study inhibition of the vascular endothelial growth factor (VEGF) pathway at both the ligand (B) and receptor (S), and platelet derived growth factor receptor (S) in mRCC. Methods: Pts with measurable mRCC, adequate organ function, and PS 0–1 were eligible. Cohorts of at least 6 pts were enrolled to define the MTD and DLT of B given IV q 2wks and S po QD on 28-day cycles. Response and toxicity were assessed after 2 cycles. Initial doses were S at 200mg BID and B at 5 mg/kg with modification based on observed toxicities. High dose pyridoxine was administered in some cohorts attempting to ameliorate hand-foot syndrome (HFS) symptoms. Results: 47/48 pts completed their 1st response evaluation. Median age was 61 yrs (35–83 ); M/F: 40/8; PS: 0/1= 32/16; 41 clear cell, 7 non-clear cell; 41 had prior nephrectomy; 6 prior IFN and 9 prior IL-2. The table summarizes dose levels explored and toxicities. Toxicities included PUD, rash, weight loss, proteinuria, hypertension, and HFS with no evidence of microangiopathy. Three pts had late vascular events after >12 mos of treatment (TIA, AMI) Pryidoxine did not ameliorate HFS. Only 4/48 pts stopped therapy due to toxicities. MTD was S 200 mg PO QD and B 5 mg/kg IV Q 2 wks. 46/48 pts were evaluable for response. Twenty-one of 46 (46%) had PR by RECIST, including 2 pts with sarcomatoid RCC. Additionally, 23 pts had SD and 1 PD at 1st eval.with 1 dying from disease progression prior to 1st eval. Median time to progression (TTP) was 11.2 months with 10 pts (21%) progression-free at 18 mos. Conclusions: While toxicities led to a MTD with lower doses of each agent, B + S had impressive antitumor activity based on both OR and TTP. B appears to significantly increase S-related toxicity, especially HFS. We have opened a Phase II trial with correlative and PK studies for S and B to investigate the mechanism of enhanced S-related toxicity. The combination has been incorporated into E2804 (BeST) a multi-arm Phase II trial of combination regimens. The study was supported by U01 CA099177 and CTEP-NCI.