Phase I dose-escalation trial of paclitaxel and ifosfamide in patients with advanced non-small cell lung cancer.

This phase I dose-escalation study was undertaken to determine the maximum tolerated doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and ifosfamide that could be administered without growth factors to previously untreated patients with non-small cell lung cancer. Forty patients with advanced non-small cell lung cancer were treated with a 3-hour infusion of paclitaxel and a 1-hour infusion of ifosfamide, repeated every 3 weeks. Groups of three patients each entered at escalating dose levels in a traditional phase I design. Starting doses were paclitaxel 100 mg/m2 and ifosfamide 3 g/m2; all patients received premedication with dexamethasone and diphenhydramine, and some also received a 5-HT3 blocker. Dose escalation was permitted only after full toxicity assessment had been completed for two cycles for all patients at a dose level. Dose escalation of paclitaxel continued to 225 mg/m2 without dose-limiting toxicity, but further escalation was not attempted because of the known likelihood of neurotoxicity above this dosage. Instead, ifosfamide was increased to 4 g/m2 for the final dose level. At these doses, dose-limiting myelosuppression was not seen, and there was only one episode of febrile neutropenia in 162 treatment cycles. Drug-related ifosfamide toxicities included gross hematuria and confusion in one patient each; paclitaxel-related symptoms included flu-like syndrome in most patients, arthralgia and/or myalgia in eight and 25 patients, respectively, and paresthesia in 14 patients. Despite premedication, 15 patients experienced grade 1 hypersensitivity reactions. Partial response was seen in 21% of patients (confidence interval, 9.3% to 36.5%), and the median duration of response was 5.9+ months (range, 3 to 14 months). The median survival was 9.1 months (range, 1 to 12 months). In summary, outpatient paclitaxel given over 3 hours and single-dose ifosfamide given over 1 hour may be combined safely without hematopoietic growth factors for the treatment of patients with non-small cell lung cancer. The recommended doses for phase II study are paclitaxel 225 mg/m2 and ifosfamide 4 g/m2, every 3 weeks.