Phase I study of dasatinib in combination with capecitabine, oxaliplatin, and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.

Abstract

3586 Background: SRC is a non-receptor tyrosine kinase involved in normal and tumor cell signaling functions including cell proliferation, angiogenesis and survival. Dasatinib (D) is a potent inhibitor of SRC kinase activity. Preclinical data suggests the addition of D to standard chemotherapy agents for colon cancer may increase anti-tumor activity. We evaluated D in combination with capecitabine (C), oxaliplatin (O) and bevacizumab (B) in a phase I dose escalation study followed by an expanded cohort in first-line colorectal. Methods: For dose escalation, eligible patients had advanced solid tumors with adequate organ function and no increased risk for class-related toxicities. B and O were given intravenously, and C and D were orally administered; cycle length was 21 days. C was dosed at 850 mg/m2 on days 1-14; O was dosed at 130 mg/m2 and B was dosed at 7.5 mg/kg on day one of each cycle. D was dosed at 50 mg twice daily in cohort one and 70 mg once daily in cohort -1. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: Dose escalation is complete with 10 subjects evaluable for DLT toxicity and 11 subjects evaluable for efficacy. Two DLTs were observed out of 4 evaluable subjects in cohort one. Six evaluable subjects were enrolled in the -1 cohort with 1 DLT. Two subjects have been enrolled in the expanded cohort. Possible grade ≥3 treatment-related adverse events (AEs) included neutropenia, febrile neutropenia, anorexia, diarrhea, fatigue, anemia, dehydration and grade 5 GI-perforation. One non-treatment related death was due to disease progression. D-related nausea, anorexia and fatigue were responsive to low dose oral steroids; fluid retention was responsive to diuretics. Of 13 subjects evaluable for efficacy, 3 subjects had a partial response (PR), 6 had stable disease (SD) as best response. Conclusions: D in combination with C, O and B is well-tolerated with a toxicity profile similar to standard C, O and B.The recommended phase II dose is C at 850 mg/m2 on days 1-14, O at 130 mg/m2 and B at 7.5 mg/kg on day one of each cycle, and D at 70 mg once daily. Enrollment in the expanded cohort of first-line colorectal is nearing completion.