A phase I trial of high-dose paclitaxel, cyclophosphamide and mitoxantrone with autologous blood stem cell support for the treatment of metastatic breast cancer

The aim of this phase I study was to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and efficacy of a new combination of cyclophosphamide (6 g/m2), mitoxantrone (70 mg/m2), with dose escalation of paclitaxel (TaxolR) at a starting dose of 250 mg/m2 given intravenously over 3 h in a transplantation setting. Patients with metastatic breast cancer and chemosensitive disease were eligible. The autologous blood stem cell re-infusion and subsequent recovery occurred in an out-patient setting. 50 patients were enrolled, but 10 withdrew. 40 completed the entire protocol. At 400 mg/m2 paclitaxel administered over 3 h, 3 of 6 patients experienced serious adverse events: approximately 20-40 min after completion of infusion, diaphoresis, bradycardia mild hypotension and diarrhoea occurred; 2 patients lost consciousness for a few minutes. An extended infusion schedule delivering 400 mg/m2 paclitaxel over 6 h rather than 3 h was initiated at this level without patients experiencing this DLT. At the next dose of 450 mg/m2 paclitaxel over 6 h, the same DLT was seen as at 400 mg/m2 paclitaxel over 3 h and, therefore, MTD was reached. Time to recovery for the absolute neutrophil count > or = 0.5 x 10(9)/l was 10-19 days (median 12 days); and for platelets > or = 20 x 10(9)/l was 18-20 days (median 11.5 days). 21 patients developed neutropenic fever that required intravenous antibiotics and re-admission; the transfusion frequency for packed red blood cell was 0-5 units (median 2 units) and for platelets, 1-5 encounters (median 2). 13 complete responses, 1 patient with no evidence of disease and 19 partial remissions were documented. The dose of 400 mg/m2 at an infusion rate of 6 h will be used for the ongoing phase II study to evaluate efficacy and toxicity further.