Phase I Study Of Dasatinib In Combination With Bevacizumab In Advanced Solid Tumors

TPS163 Background: Despite the tremendous promise of new signal transduction and angiogenesis inhibitors, these targeted drugs have met with mixed results so far in the clinic. In solid tumors, inhibition of multiple targets may be necessary for significant clinical effects. Dasatinib is an inhibitor of all SRC-family kinases, as well as BCR-ABL, c-KIT, multiple EPH-family kinases, PDGFβ receptor and other tyrosine kinases. Bevacizumab is a humanized IgG1 monoclonal antibody that binds all biologically active isoforms of human vascular endothelial growth factor (VEGF) with high affinity. Attenuation of both c-Src and VEGF pathways simultaneously provides the potential for synergistic antitumor activity, as there is a extensive interaction between these pathways. VEGFR transmits its downstream signal through multiple pathways involving c-Src (including activation of the prosurvival FAK pathway). Alternatively, VEGF production is known to be Src-mediated (including via STAT5 signaling). Thus, inhibition of c-Src may block the VEGF angiogenic stimulus in at least two independent ways. As they have a largely non- overlapping toxicity profile, we have initiated a Phase I trial combining these two drugs. Methods: Objectives: Determine the safety and toxicity of the combination of dasatinib and bevacizumab. Determine biochemical changes in the src-FAK and src-PLC-g and VEGF signal transduction pathways in tumor and stromal cells in response to treatment at the MTD. Eligibility: Adults with histologically documented solid tumor malignancy that is metastatic or unresectable and for which standard curative therapies do not exist or are no longer effective. Design:This is an open-label phase I dose escalation study. Dasatanib will be orally administered daily and bevacizumab will be given intravenously every two weeks. At the MTD, pharmacodynamic endpoints related to signal transduction pathway alterations and tumor vascularity will be measured with tumor biopsies and DCE-MRI. Approximately 48 patients will be needed to achieve the objectives of the trial. No significant financial relationships to disclose.