Correlative studies of a phase I trial of combination anti-vascular endothelial growth factor (VEGF) therapy with sorafenib and bevacizumab

3545 Background: We targeted the VEGF pathway in a phase I trial combining bevacizumab, a monoclonal antibody to VEGF, with sorafenib, a multikinase inhibitor of VEGF-receptor-2 and Raf-kinase. We hypothesized that the combination would result in suppression of angiogenesis and tumor growth. Methods: Eligible patients had advanced solid tumors, ECOG 0–1, good organ function, and no prior treatment with either agent. Sorafenib 200 mg BID and bevacizumab 5 mg/kg q2wks every 28d was the MTD on which 28 pts were enrolled. Patients were randomized to receive single agent sorafenib or bevacizumab for one cycle followed by combination therapy with both agents thereafter. Serum for VEGF, IL-6, and IL-8 analysis was drawn on-study and then monthly. Angiogenic potential of patient sera was measured using rat aortic ring assay (RARA) with pre-treatment and cycle 4 sera. A Wilcoxan rank sum test was used to evaluate the difference between values at the indicated time points. Plasma for pharmacokinetics (PKs) was drawn during cycles 1–2 and tested with a 1-way ANOVA on log-AUC and Cmax values. Tumor biopsies obtained on-study, 2 wks, and 6 wks are being analyzed for proteomic endpoints with reverse phase tissue arrays (RPAs). Results: 28 patients have received a total of 204 cycles of treatment. 7/28 patients had partial responses or disease stabilization >6 mo (median 14: 6–26+) by RECIST criteria. Detailed and response data were previously reported. Circulating VEGF increased with sorafenib+bevacizumab treatment (p < 0.01) but did not correlate with disease response; Il-6 and IL-8 levels did not change with treatment. RARA showed no correlation between neovasculature and disease response. No PK interactions between sorafenib and bevacizumab were observed. Tumor specimen processing and RPA optimization have been completed; measurements of changes in signal protein activation will be completed by time of presentation. Conclusions: Sorafenib+bevacizumab results in modified circulating pro-angiogenic cytokine production with no effect in in vitro angiogenesis assays. There was no measurable PK interaction between the two agents. Analysis of modification of signal protein activation status by sorafenib+bevacizumab is pending. No significant financial relationships to disclose.