Phase I trial of 3-hour infusion of paclitaxel with or without granulocyte colony-stimulating factor in patients with advanced cancer.

Abstract

PURPOSE We conducted a phase I trial of a 3-hour infusion of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) to identify the maximum-tolerated dose of Taxol as a 3-hour infusion with and without granulocyte colony-stimulating factor (G-CSF) support. MATERIALS AND METHODS Thirty-five patients with advanced, untreatable malignancies were treated with a 3-hour infusion of Taxol once every 3 weeks. Groups of three patients were entered at escalating dose levels of Taxol in a traditional phase I design in each of two parallel arms: arm A, without G-CSF, and arm B, with G-CSF. Patients assigned to the G-CSF arm received G-CSF 5 micrograms/kg/d subcutaneously starting on day 2 for 9 to 14 days. All patients were pretreated with dexamethasone, diphenhydramine, and ranitidine, and were monitored continuously for cardiac arrhythmias during the first treatment. RESULTS Dose-limiting myelosuppression with Taxol without G-CSF was observed at the 250-mg/m2 dose level. The dose-limiting toxicity for Taxol with G-CSF was peripheral neuropathy at the 300-mg/m2 dose level. One of 35 patients (2.8%) had a grade 3 anaphylactic reaction at 250 mg/m2. No clinically significant cardiac arrhythmias were documented. Twenty-seven of 111 courses (24%) were associated with grade 3 arthralgias or myalgias requiring narcotics for pain control. Taxol plasma concentrations declined in a triexponential fashion, with a final elimination half-life of 10 to 12 hours. The peak Taxol plasma concentrations and total area under the curve (AUC) increased with increasing doses of Taxol, although this increase appeared to be somewhat nonlinear. CONCLUSION The maximum dose of Taxol recommended for phase II and III studies, when administered as a 3-hour infusion alone and with G-CSF support, is 210 mg/m2 and 250 mg/m2, respectively. No increased incidence of hypersensitivity reactions or other side effects were observed, with the possible exception of arthralgias and myalgias. If ongoing trials demonstrate that a 3-hour infusion is as efficacious as a 24-hour infusion, we conclude that with proper monitoring and premedication, high-dose Taxol can be safely administered in the outpatient setting.