Phase I study of paclitaxel (TaxolTM) and ifosfamide in previously untreated patients with advanced non-small-cell lung cancer: A study of the National Cancer Institute of Canada Clinical Trials Group

BACKGROUND:: Paclitaxel (Taxol^TM) and ifosfamide are among the most activesingle agents for the treatment of non-small-cell lung cancer.We undertook this phase I dose escalation study to determinethe maximum tolerated doses of these drugs which could be administeredwithout growth factors to untreated patients with tumours ofthis type. PATIENTS AND METHODS:: Forty patients with advanced non-small-cell lung cancer weretreated with a 3-hour infusion of paclitaxel and a 1-hour infusionof ifosfamide every 3 weeks. Groups of 3 patients were enteredat escalating dose levels in traditional phase I design. Startingdoses were paclitaxel, 100 mg/m², and ifosfamide 3 g/m², andall patients received premedication with dexamethasone, diphenhydramineand a 5-HT3 blocker. Dose escalation occurred only after fulltoxicity assessment for 2 cycles for all patients in the doselevel. RESULTS:: Dose escalation of paclitaxel continued to 225 mg/m² withoutdose-limiting toxicity, but further escalation was not attemptedbecause of the known likelihood of neurotoxicity above thislevel. Instead, ifosfamide was increased to 4 g/m² for the finallevel. At these doses, dose-limiting myelosuppression was notseen, and there was only 1 episode of febrile neutropenia in164 treatment cycles. Drug-related toxicities of ifosfamideincluded gross hematuria and confusion in 1 patient each, andpaclitaxel-related symptoms included flu-like syndrome in mostpatients, mild to moderate arthralgia and/or myalgia in 8 and25 patients, respectively, parasthesiae in 15 patients and mildto moderate hypersensitivity reactions in 15 patients each.Partial response was seen in 20.5% of patients (CI 9.3%–36.5%). CONCLUSIONS:: The frequency of tumour cell detection in peripheral blood frompatients with advanced disease was lower than previously reported.It may be only small numbers of circulating tumour cells arepresent at any one time in the peripheral blood of patientswith malignant melanoma. If this is the case increased samplingwill improve detection fre quency. Alternatively, disseminationof melanoma through peripheral blood may be a rare event. Inour experience, RT PCR for tyrosinase mRNA as a staging testfor melanoma patients must be interpreted cautiously. Out-patient paclitaxel given over 3 hours and single-dose ifosfamideover 1 hour may be combined safely without the need for hematopoieticgrowth factors for the treatment of patients with non-small-celllung cancer. The recommended doses for phase II study are paclitaxel,225 mg/m² and ifosfamide, 4 g/m² every 3 weeks. chemotherapy, ifosfamide, non-small-cell lung cancer, paclitaxel