Updated results of phase I trial of sorafenib (S) and bevacizumab (B) in patients with metastatic renal cell cancer (mRCC).

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.,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.,47/48 pts completed their 1 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 1 eval.with 1 dying from disease progression prior to 1 eval. Median time to progression (TTP) was 11.2 months with 10 pts (21%) progression-free at 18 mos.,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. [Table: see text] [Table: see text].