摘要：

LB-69 Introduction : Dasatinib is an oral tyrosine kinase inhibitor that potently inhibits Src, a nonreceptor tyrosine kinase that affects proliferation, angiogenesis, migration, invasion, and regulation of apoptosis in colorectal cancer cells. Dasatinib is approved for treatment of refractory CML based on its ability to inhibit Bcr/Abl activity. Src activation is frequent in metastatic colorectal cancer and has been associated with chemotherapy resistance. We have shown previously that Src inhibitors are synergistic with both the EGFR antibody cetuximab and with oxaliplatin in vitro and in vivo . Building on these preclinical findings, a combination study of dasatinib with FOLFOX and cetuximab was developed. Methods : The study reported is a single institution, phase I study in patients with previously-treated metastatic colorectal cancer. Primary objectives of this study are to determine the maximum tolerated dose, toxicity, and pharmacodynamics of the combination regimen. Based on the 3+3 design, cohorts of 3-6 patients receive FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and 5-FU 400 mg/m2 followed by 5-FU 2,400 mg/m2 46-hour infusion every two weeks) with cetuximab (400mg/m2 initial dose then 250mg/m2 weekly) and escalating doses of dasatinib (at cohorts of 100, 150, 200mg PO daily). Results : 12 patients have been enrolled to date; 6 in the 100mg cohort, and 6 in the 150mg cohort. One dose-limiting toxicity each was observed in the 100mg and 150mg dasatinib cohorts (grade 4 and 3 fatigue, respectively). Other toxicities in all cycles in this heavily pretreated population have included grade 3 hypophosphatemia, neutropenia, and anemia. The third cohort of 200mg is currently enrolling. Of the 8 evaluable patients, three patients previously treated with both FOLFOX and an EGFR monoclonal antibody have radiographic evidence of response. Two patients have confirmed partial response. Conclusions: Dasatinib at a dose of 150mg daily in combination with FOLFOX and cetuximab is safe with promising early signs of clinical activity in previously treated patients. Accrual is ongoing at higher doses with pharmacodyanamic studies incorporated. MTD, toxicities, and updated preliminary efficacy results will be reported.

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