Phase I-II study of pegylated liposomal doxorubicin combined with weekly paclitaxel as first-line treatment in patients with metastatic breast cancer

Objectives: Pegylated liposomal doxorubicin (PLD) appears to be as active as doxorubicin in first-line metastatic breast cancer (MBC) patients, with lower cardiac toxicity. This phase I-II trial aimed to determine the dose limiting toxicity (DLT) and recommended dose (RD) of a first-line combination of PLD and weekly paclitaxel. Methods: MBC patients received PLD on day 1, administered over 60 minutes IV. (starting dose 30 mg/m(2), escalation by 5 mg/m(2) increments), and paclitaxel on days 1, 8, and 15. Initially (schedule A), paclitaxel was administered over 60 minutes (starting dose 80 mg/m(2), 10 mg/m(2) increments), then (schedule B) over 24 hours on day 1 (at a dose of 70 mg/m(2), 10 mg/m(2) increments), and in a 60 minute IV infusion at a fixed dose of go mg/m(2) on days 8 and 15. Pharmacokinetics were assessed during cycle 1 in schedule B. Results: Thirty patients were treated (schedules A = 9; B = 21). Because of cutaneomucous toxicities in all patients in schedule A with discontinuation in 5 patients, schedule B was explored. Two DLTs (febrile neutropenia) occurred, with PLD 35 mg/m(2) with paclitaxel go mg/m(2) day 1 and go mg/m(2) days 8 and 15 identified as recommended dose. Pharmacokinetic evaluation revealed an interaction, with increased levels of free doxorubicin and PLD during the paclitaxel infusion. Conclusions: This combination according to schedule and dosages results in cutaneomucous and hematological toxicity, probably because of a pharmacokinetic interaction, which is poorly compatible with a good quality of life for MBC patients.