Dasatinib in Combination With Bevacizumab to Treat Advanced Solid Tumors

BACKGROUND: Dasatinib is an inhibitor of SRC family kinases, BCR-ABL, c-KIT, EPHA2 and PDGF beta receptor. Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically active isoforms of human vascular endothelial growth factor (VEGF, or VEGF-A) with high affinity (k(d) = to 1.1nM). This Phase I trial is open to patients with all solid tumors. OBJECTIVES: Determine the safety and toxicity of the combination of dasatinib and bevacizumab. Determine biochemical changes in the src-FAK and src-PLC-gamma. and VEGF signal transduction pathways in tumor and stromal cells in response to treatment at the MTD, in a pilot fashion, if those changes are statistically significant. 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. Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks. All patients enrolling in Group 2 must have at least one lesion amenable to biopsy. ECOG performance status 0 or 1 and adequate organ and marrow function. DESIGN: Group 1 will receive dasatinib and bevacizumab together at the start of study in a dose escalation fashion. Group 2 will be randomized as to which agent they receive for cycle one. Cycles 2 and beyond are treated using both agents. Tumor biopsies will be obtained from patients in Group 2 before treatment, two weeks into mono-therapy, and two weeks into combinatorial therapy. DCE-MRI studies will be obtained on patients in Group 2 before treatment, two weeks into monotherapy, four weeks into monotherapy, and two weeks into combinatorial therapy. Patients will be evaluated for toxicity in clinic every 2 weeks for Cycles 1 and 2, and then every 4 weeks. For patients who have been on the study over 2 years, the cycle may be lengthened to 6 or 8 weeks at the discretion of the investigator. Patients will be evaluated for response every 8 weeks using the RECIST criteria. After patients have completed 2 or more years on study, the interval may be lengthened to 12 or 16 weeks at the discretion of the investigator. Approximately 48 patients will be needed to achieve the objectives of the trial.