Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naive patients with advanced non-small-cell lung cancer

Background. Gemcitabine (GEM) and paclitaxel (TAX) are active, non-cross-re sistant drugs in non-small-cell lung cancer (NSCLC). We performed a phase I study to determine the maximum-tolerated dose (MTD), antitumor activity an d pharmacokinetics of GEM and TAX given weekly in chemo-naive patients with advanced NSCLC. Patients and methods: Escalating doses of GEM (800-2000 mg/m(2)) and TAX (6 0-100 mg/m(2)) were administered on days 1, 8, 15 every 4 weeks to 35 patie nts with advanced NSCLC. Plasma pharmacokinetics of TAX and GEM was assesse d at the three higher dose-levels. Results: Dose-escalation was discontinued in absence of MTD because of incr eased cumulative toxicity leading to dose modification or treatment delay a t levels 6 and 7 (TAX 100 mg/m(2) plus GEM 1750 and, respectively, 2000 mg/ m(2)). Hematological toxicity included grade 4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycle and febrile neutropenia in three cyc les. Maximal non-hemathological toxicity was grade 3 elevation in serum tra nsaminases and grade 2 neuro-sensory toxicity in 8% and 5% of cycles, respe ctively. At the two higher dose-levels a non-linear pharmacokinetics of GEM was observed with a remarkable variability of C-max and AUG. No pharmacoki netic interactions were reported. Objectives responses were seen at all dos e levels, with an overall response rate of 43% (95% confidence interval (95 % CI): 25.5%-62.6%) in 30 evaluable patients. Conclusions: The weekly administration of GEM and TAX is very well tolerate d, and has shown promising antitumor activity in NSCLC. In view of the cumu lative toxicity and of the pharmacokinetic profile of GEM, doses of 1500 mg /m(2) of GEM and 100 mg/m2 of TAX are recommended for phase II studies.