Paclitaxel and carboplatin with and without filgrastim support in patients with metastatic non-small cell lung cancer

Paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ) and carboplatin have each shown activity against non-small cell lung cancer and they are synergistic in vitro. We thus designed a phase I study to define the maximum tolerated dose and dose-limiting toxicity of the combination with and without filgrastim support. With an initial fixed dose of paclitaxel 135 mg/m² given as a 24-hour infusion, carboplatin was administered in escalating doses in cohorts of three patients, based on a target area under the concentration-time curve (AUC) of 5, 7, 9, or 11 using Calvert's formula: dose (mg) = target AUC x (glomerular filtration rate + 25). Dose escalations were based on course I toxicities. Filgrastim 5 μg/kg was administered with the first cycle only after grade 4 neutropenia occurred in two of three patients at the prior dose level. One hundred five courses of paclitaxel and carboplatin have been administered in 26 patients. Dose-limiting toxicity (grade 4 neutropenia) occurred in two patients at level 2 (cycle I). Filgrastim was instituted thereafter with cycle I for the next four levels. Grade 4 thrombocytopenia was seen at level 4; thus, the carboplatin dose was de-escalated in the next level, but the paclitaxel dose was escalated. The regimen has been well tolerated. One patient had a complete response and 12 had partial responses, for an overall response rate of 50%. There is a suggestion of a dose-response effect with both paclitaxel and carboplatin. The combination of paclitaxel and carboplatin is active in non-small cell lung cancer, and the recommended phase II doses for the combination without filgrastim support are paclitaxel 175 mg/m² as a 24-hour infusion with the carboplatin dose based on a target AUC of 7. The phase II dose with filgrastim support will be defined as dose escalation of paclitaxel continues.