BACKGROUND Ifosfamide and paclitaxel are active drugs in the management of non-small-cell lung cancer. We have performed a phase I study using a fixed dose of ifosfamide with escalating doses of paclitaxel, with G-CSF support, in an effort to determine the maximum tolerated dose (MTD) of paclitaxel in this combination, and to describe the dose-limiting toxicities of the combination at the recommended phase II dose of paclitaxel. We also studied the feasibility of delivering the paclitaxel as a one-hour infusion at the recommended phase II dose. METHODS Thirty-one patients were treated, 25 with stage IV disease, and 6 with stage IIIB disease. Ifosfamide was administered at a dose of 1.6 g/m2 i.v. bolus daily x 3 days, with mesna uroprotection. Paclitaxel was administered as a 24-hour infusion at dose levels of 135, 170, 200, 250, and 300 mg/m2; six patients were treated with a one-hour infusion, at a dose of 250 mg/m2. G-CSF, 5 micrograms/kg, was administered subcutaneously on days 4 through 10, or until the absolute neutrophil count exceeded 4000/microliters. Cycles were repeated every 21 days. RESULTS The dose-limiting toxicity was granulocytopenia, which increased with increasing dose levels of paclitaxel. The MTD was 300 mg/m2 of paclitaxel, and the recommended phase II dose 250 mg/m2 administered as a 24-hour infusion. Other toxicities were generally mild, with only 5 patients demonstrating grade 3 neurotoxicity and 5 with grade 3 thrombocytopenia. Partial responses were seen in seven patients (23%), all in the 18 patients who received dose levels of 250 mg/m2 or higher. CONCLUSIONS Ifosfamide plus paclitaxel is an active treatment regimen in advanced non-small-cell lung cancer, and compares favorably with the results of cisplatin-based chemotherapy. A phase II study is in progress by the Cancer and Leukemia Group B, in an effort to better characterize the tolerance of the regimen, as well as its effect on tumor response and survival.