A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer

Background: SRC plays an important role in the pathogenesis of metastatic breast cancer (MBC). In preclinical models, paclitaxel and the oral SRC inhibitor dasatinib showed greater antitumor activity than either agent. To determine the maximum tolerated dose of this combination, we conducted a phase I study. Patients and methods: Patients with MBC; Eastern Cooperative Oncology Group performance status of zero to one; normal hepatic, renal and marrow function were eligible. Paclitaxel 80 mg/m ² was given 3 weeks of 4. The starting dasatinib dose was 70 mg and was increased, using a standard 3 + 3 dose-escalation scheme. Results: Fifteen patients enrolled (median age 54 years, range 35-74). No dose-limiting toxic effects (DLTs) occurred at dasatinib doses of 70-120 mg. One DLT (grade 3 fatigue) occurred in the dasatinib 150-mg cohort, which was expanded (six patients) with no further DLTs. However, due to cumulative toxic effects (rash, fatigue, diarrhea), the recommended phase II dose is dasatinib 120 mg. Of 13 assessable patients, a partial response was seen in 4 patients (31%), including 2 patients previously treated with taxanes; all received ≥120 mg dasatinib. An additional five patients (29%) had stable disease. Conclusion: In combination with weekly paclitaxel, the recommended phase II dose of dasatinib is 120 mg daily and preliminary activity has been seen in patients with MBC.