122 O - A phase I trial of epirubicin (E) and paclitaxel (P) in patients with metastatic breast cancer (MBC)

We have performed a phase I study In MBC patients (pts) to determine the maximum tolerated dose (MTD) of P to be administered in association with E at a fixed dose of 90 mg/sqm. P was given i.v. by a 3 hrs infusion, immediately after E, starting from a dose of 135 mg/smq and escalating by 20 mg/sqm for each dose level until DLT. DLT was defined as follows: absolute neutrophil count (ANC) 7 days or 3 days, febrile neutropenia or any G3 non hemalologic toxicity. G-CSF was allowcd to accelerate recovery of G4 neutropenia lasting more than 3 days. An Holter EKG was performed at each course and the left ventricular ejection fraction (EF) was evaluated every 2 courses by echo-doppler. 32 patiens with the following characteristics have been treated: median age 54 (34–66) yrs; median (ECOG) PS 0 (0-1); 84% of the patients had failed adjuvant chemotherapy (including anthracycline in 14 cases), The dominant metastatic sites were: viscera 20 pts (62%). sort lissue 11 pts (34%), and bone 1 pts (3%). The DLT is febrile neutropenia which occurred at the first course in 2 8 pts patients treated with P 225 mg sqm. A total of 176 courses have been administered; a G4 neutropenia occurred in 66% of the courses, lasting a median of 4 days (range 1–8). G-CSI (300 μg die) was given in 34% of the courses for a median of 5 days range (2-12). Most significant non hematologic toxicities were: a G 1-2 mucositis in 29% of the courses and a G 1-2 peripheral neuropathy in 56% of the pts. The cardiac toxicity was low: only 2 pts showed a drop of the EF below 50% after 6 courses; no sign of congestive heart failure was observed. The overall response rate is: 76% with 14% of complete responses (95% C.I. 56-90%). In conclusion we have demonstrated that the combination of E and P is feasible. devoid of cardiac toxicity and active in a population of pts who failed adjuvant chemotherapy. Our recommended phase II dose of P is 200 mg/sqm.