Phase I study of Doxil and vinorelbine in metastatic breast cancer

Background: Vinorelbine and Doxil (liposomal doxorubicin) are active chemotherapeutic agents in metastatic breast cancer. A phase I study was designed to evaluate combination therapy.Patients and methods: Thirty women with metastatic breast cancer were enrolled. Dose-limiting toxicity was determined through a dose escalation scheme, and defined for the first treatment cycle, only. Pharmacokinetic studies were performed during the first cycle of treatment.Results: In the first cohort of Doxil 30 mg/m² day 1 and vinorelbine 25 mg/m² days 1 and 8, patients experienced severe neutropenia. Vinorelbine administration was changed thereafter to days 1 and 15 of each cycle. Dose limiting toxicity was observed at Doxil 50 mg/m² and vinorelbine 25 mg/m². Doxil 40 mg/m² and vinorelbine 30 mg/m² was defined as the maximally tolerated dose. Few toxicities (principally neutropenia) were seen at this dose level, with the notable absence of significant nausea, vomiting, or alopecia. Though 63% of patients had received prior anthracycline-based chemotherapy, only one patient developed grade 2 cardiac toxicity. Pharmacokinetic studies revealed prolonged exposure to high doxorubicin concentrations for several days following Doxil administration.Conclusions: Combination chemotherapy with Doxil and vinorelbine affords treatment with two active drugs in women with metastatic breast cancer, and appears to have a favorable toxicity profile. A schedule of Doxil 40 mg/m² day 1 and vinorelbine 30 mg/m² days 1 and 15 given every 28 days is recommended for phase II studies.