Phase I/II investigation of paclitaxel, ifosfamide and carboplatin for advanced non-small-cell lung cancer

Background: The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen. Patients and methods: Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m(2) as a 1-h infusion on day 1 with carboplatin at an area under the concentration-time curve (AUC) of 6 mg.min/ml on day 2. For dose level 1, ifosfamide was administered at a dose of 2 g/m(2) on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m(2) on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg.ml/min. Therapy for dose levels I and III included filgrastim support (5 mug/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10000/mul. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimen's activity and tolerability. Results: Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered in the initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase H dose. A total of 49 patients were treated at the recommended phase II dose. The predominant nonhematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively. Conclusions: The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.