Dasatinib In Combination With Trastuzumab And Paclitaxel In First Line Treatment Of Her2-Positive MBC Patients

Eligible patients will be enrolled and treated with 4-week cycles of trastuzumab 2 mg/kg IV weekly (following a loading dose of 4 mg/kg in cycle 1) and paclitaxel 80 mg/m2 weekly x 3 weeks followed by a rest period of 7 days. Dasatinib will be administered orally in two dose levels 100 and 140 mg once daily (a -1 dose level is included just in case dose de-escalation is needed). Treatment will be repeated on Day 1 of a 28-day cycle in all patients (both in the phase I as in the phase II) until radiographic or symptomatic progression or unacceptable toxicity occurs. Only in the phase I and in all patients included in every different dose level, the first cycle will last 38 days. Primary Objective: * To determine the maximum tolerated dose (MTD) and recommended phase II dose (RPD) of dasatinib in combination with fixed doses of trastuzumab and paclitaxel in HER2-positive MBC patients (Phase I). * To determine the efficacy, measured by objective response rate (ORR) in HER2-positive MBC patients with measurable disease (Phase II). Secondary Objective(s): * To characterize the safety of the combination (in both phase I and phase II). * To evaluate the Clinical Benefit Rate (CBR), Time to Progression (TTP), Progression Free Survival (PFS) and Response Duration (RD) (in the phase II). * To evaluate the pharmacokinetics (PK) of the combination (in the phase I and selected patients in the phase II if necessary). * To evaluate molecular characteristics that may be predictive of the activity (or lack of) and any correlation between the biological activity of the study treatment and the disease outcome. Exploratory objective: • To explore the correlation between the lymphocytosis and efficacy. Sample Size: Phase I: following the 3+3 rule, a minimum of 6 and a maximum of 12 patients will be recruited. Phase II:Assuming 10% drop-out rate, 48 patients are required to enter the study. The duration of the study, from first patient visit to last patient visit will be approximately 42 months.