Phase i study of prolonged-Infusion gemcitabine combined with cyclophosphamide in patients with metastatic carcinoma of the breast: Tolerability of an optimal dose schedule

Background: A phase I study was initiated to determine the maximum tolerated dose (MTD) of prolonged-infusion gemcitabine combined with cyclophosphamide in patients with metastatic breast carcinoma (MBC). Methods: Patients with MBC were treated with gemcitabine infusion at 10 mg/m ²/min and cyclophosphamide by intravenous piggyback injection, 4 h after initiation of the infusion. We treated 3-6 patients at a particular dose level until the MTD was determined. Results: Overall, 44 patients received a total of 197 courses of therapy. Both drugs were given on days 1, 8 and 15 to 14 patients (68 courses). Delayed white blood cell recovery necessitated first protocol amendment to drop cyclophosphamide on days 8 and 15 in 9 patients (43 cycles). A second amendment was needed to drop gemcitabine on day 15 because of thrombocytopenia in 21 patients (86 courses). The dose-limiting toxicity was thrombocytopenia. The MTD of an optimal dose schedule was 800 mg/m² gemcitabine infused at a rate of 10 mg/m²/min on days 1 and 8, and 400 mg/m² cyclophosphamide, by intravenous piggyback injection, on day 1, 4 h after initiation of the gemcitabine infusion. Conclusions: The MTD can be given safely every 4 weeks to patients with MBC. Phase II studies are warranted to evaluate the clinical activity of this therapy.