A phase I dose expansion cohort study of dasatinib in combination with bevacizumab in advanced solid tumors (NCT01445509).

Abstract

2585 Background: Dasatinib is a known inhibitor of the SRC family kinases and is approved for use in chronic myelogenous leukemia. Bevacizumab inhibits angiogenesis, binding to human vascular endothelial growth factor (VEGF, or VEGF-A) with high affinity. VEGF receptor signals intracellularly via a cascade regulated by SRC. Given the presence of this signaling pathway in both tumor cells and endothelial cells, we hypothesized that attenuation of both SRC and VEGF simultaneously would have synergistic antitumor activity. We previously reported the maximum tolerated dose (MTD) of dasatinib 100mg daily with bevacizumab 10mg/kg q2wk in patients with advanced solid tumors. We now report clinical activity of the combination, and translational endpoints of an expansion cohort. Methods: This is a phase 1 dose escalation with non-randomized expansion cohort. We monitored safety, and response was assessed every 8 weeks using RECIST criteria. Correlative endpoints include blood flow by dynamic MR imaging, endothelial cell density by CD31 immunohistochemistry, functional angiogenic potential by plasma cytokines and rat aortic ring assay, and tumor cell activation state by phosphoprotein analysis. Results: We enrolled 39 patients at the MTD for a total of 50 patients on study, including both the dose escalation and dose expansion phases. No patient experienced dose limiting toxicities during dose escalation. The most common adverse events were grade 2 hypertension and proteinuria. By RECIST, 5 (10%) patients had a partial response, and stable disease was seen in 29 (58%) of patients with a range from 12-145+ weeks on study. We had two exceptional responders with endometrial carcinoma who continue on study to date (112 weeks and 145 weeks). Translational endpoints were correlated with clinical outcome. Conclusions: Bevacizumab and dasatinib are safe in combination, with potential clinical activity. This combination warrants further investigation in solid tumors. Ongoing translational research using specimens from exceptional responders will suggest potential biomarkers of clinical benefit, to be tested in future prospective clinical trials. Clinical trial information: NCT01445509.