First line treatment of HER-2/neu positive advanced breast cancer patients with liposomal doxorubicin (Myocet), docetaxel and trastuzumab. A phase I-II study

Abstract

10744 Background: Our preclinical data showed synergic effect of Adriamicyn followed by Taxotere in BC cell lines. The combination of anthracyclines, taxanes and trastuzumab could potentially obtain a high number of objective responses and a consistent impact on the time to progression and on the overall survival. The aim of this phase I-II study was to assess the maximum tolerated dose (MTD) of liposomal doxorubicin (Myocet-M) and Taxotere (T) in combination with Herceptin (H). A reduction of cardiotoxicity risk without reducing chemotherapy activity was supposed. Methods: Locally advanced or metastatic her-2/neu positive BC patients (pts) with LVEF ≥ 60% were enrolled in an open, single arm, non-randomized phase I-II escalation trial in 3 to 6 pts/cohorts. The treatment schedule was: M 50 mg/m2 (or 60, depending on dose level assignment) on day 1, T 30 mg/m2 on day 2 and 9, H 4 mg/kg on day 2 followed by weekly dose of 2 mg/kg, every three weeks. MTD dose was identified on the basis of DLT defined according to WHO grade classification of toxicity or specific conditions of LVEF decrease. A pharmacokinetic (PK) analysis of doxorubicin until 72 hours after M administration was planned. Results: Seven pts, median age 63 yrs, were enrolled. Four pts were allocated to dose level 50/30 (M/T) and other 3 pts to dose level 60/30. At the dose level 60/30 febrile neutropenia (DLT) occurred in 2 pts. Other 2 pts experienced febrile neutropenia (no DLT). One event of tachicardia (WHO grade 1) at maximum tolerated dose level was completely recovered without treatment. LVEF values were unmodified. Six patients were enrolled in the PK analysis. T pharmacokinetic data obtained on day 2 and on day 9 were not statistically different. Conclusions: The MTD was defined at M 50 mg/m2 in combination with T 30 mg/m2. The cardiac tolerability was good, with no significant change in LVEF values from baseline to the end of therapy. PK data indicated that the residual concentration of M found on day 2 was did not influence T pharmacokinetics, according to literature data. A phase II study is ongoing to assess activity and PK interactions between drugs. Till now 25 patients have been enrolled, the planned sample size is 45. No significant financial relationships to disclose.