A phase I trial of 3-hour infusions of paclitaxel (Taxol) with or without granulocyte colony-stimulating factor.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a novel antitubulin agent derived from the bark of the Pacific yew tree, may be one of the most active single agents in our chemotherapy armamentarium. Concern over acute hypersensitivity reactions has resulted in an administration schedule consisting of a 24-hour infusion. We conducted a phase I trial of a 3-hour infusion of paclitaxel to determine whether a 3-hour infusion could be administered with relative safety, and to identify the maximal tolerated dose with and without granulocyte colony-stimulating factor (G-CSF) support. Thirty-five patients with advanced, untreatable malignancies received a 3-hour infusion of paclitaxel once every 3 weeks. Groups of three patients were entered at escalating dose levels in a traditional phase I design consisting of two parallel arms: arm A (without G-CSF) and arm B (with G-CSF). Dose levels of paclitaxel ranged from 210 mg/m2 to 300 mg/m2. Patients assigned to the G-CSF arm received 5 micrograms/kg/d subcutaneously starting on day 2. All patients were pretreated with dexamethasone, diphenhydramine, and ranitidine, and were monitored continuously for cardiac arrhythmias during the first treatment. The dose-limiting toxicity for paclitaxel without G-CSF was myelosuppression at the 250 mg/m2 dose level and with G-CSF was peripheral neuropathy at the 300 mg/m2 dose level. The mean absolute neutrophil count at the 250 mg/m2 dose level when administered with and without G-CSF support was 4,500/microL and 840/microL, respectively. Neuropathy appeared to be dose related and somewhat cumulative. One patient who previously received cisplatin developed a severe grade III peripheral neuropathy at the 300 mg/m2 dose level, which left her unable to use her hands and wheelchair bound; the peripheral neuropathy slowly resolved to a grade I level. Twenty-seven of III courses (24%) were associated with grade III arthralgias or myalgias, requiring narcotics for pain control. Prednisone was empirically started in 10 patients and found to be helpful in the control of these symptoms. One of 35 (2.9%) patients had a grade III anaphylactic reaction. No clinically significant cardiac arrhythmias were observed. Two previously treated patients (one with breast cancer and one with ovarian cancer) had a partial response. The maximum tolerated dose of paclitaxel administered as a 3-hour infusion was 210 mg/m2 without G-CSF and 250 mg/m2 with G-CSF.(ABSTRACT TRUNCATED AT 400 WORDS)