Abstract
1107 Background: HER-2 alteration confers enhanced anth sensitivity in MBC, although HER-2 is not a target for anth. Topoisomerase 2A (Topo) is a target for anth. Topo amplification has been reported to occur only with HER-2 amplification, in approximately 1/3 of HER-2 amplified BC, providing a rationale for anth + trastuzumab(H) therapy in MBC with co-ampified HER-2/Topo. T+anth is cardiotoxic. L may have similar single agent activity, but less cardiotoxicity than H. L competes with anth for p-glycoprotein and might enhance its activity. The cardiac safety of L + anth needed to be established. Methods: We conducted a phase I evaluation of fixed dose lapatinib (1250 mg/day) with escalating doses of epirubicin (Epi-planned dose levels I-IV :75/80/90/100 mg/m2 ) in pts with HER-2±, anth-naive metastatic BC. Epirubicin was administered q3 weeks. A minimum of 3 (if no dose-limiting toxicity) and a maximum of 6 pts were treated per dose level. Ejection fractions were performed at base line and after every second cycle; BNP and troponin after every cycle. Results: 9 pts were treated, 3 level I, 6 level II. Dose level I was declared the maximum tolerated dose following two occurrences of dose-limiting toxicity in level II. 1 pt experienced febrile neutropenia,1 had > 20% decrease in LVEF. To date there have been 3 PRs by RECIST out of 8 evaluable patients which represents a response rate of 37.5%. Conclusions: Using classic phase I criteria, the combination of L 1250 mg together with Epi 75 mg/m2 combination is relatively well tolerated and suitable for further investigation in a phase II study of HER-2+veTopo+ve MBC patients. We will conduct such a study in pts with HER-2+Topo+ metastatic BC. [Table: see text]
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