A phase I and pharmacokinetic study of weekly paclitaxel and carboplatin in patients with metastatic esophageal cancer

PURPOSE: To determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics of a fixed dose of paclitaxel followed by increasing doses of carboplatin, given weekly to patients with advanced esophageal or gastric junction cancer. EXPERIMENTAL DESIGN: Paclitaxel was administered on day 1 as a 1-h infusion at a fixed dose of 100 mg/m(2) followed by a 1-h infusion of carboplatin targeting an area under the curve (AUC) of 2-5 mg x min/ml, with cycles repeated on days 8, 15, 29, 36, and 43. RESULTS: Forty patients [36 males; median (range) age, 57 (40-74) years] were enrolled. Dose-limiting toxicity was observed at a carboplatin AUC of 5 mg x min/ml and consisted of treatment delay attributable to myelosuppression. No grade 3/4 treatment-related nonhematological toxicity was observed. The highest dose intensity (>95% of the planned dose over time) was achieved with a carboplatin AUC of 4 mg x min/ml. The mean (+/-SD) AUCs of unbound (Cu) and total paclitaxel were 0.662 +/- 0.186 and 7.37 +/- 1.33 micro M x h, respectively. Clearance of Cu was 188 +/- 44.6 liter/h/m(2), which is not significantly different from historical data (P = 0.52). Cremophor EL clearance was 123 +/- 23 ml/h/m(2), similar to previous findings. Of 37 patients evaluable for response, 1 had complete response, 19 had partial response, and 10 had stable disease, accounting for an overall response rate of 54%. CONCLUSIONS: This regimen is very tolerable and effective, and the recommended doses for additional studies are paclitaxel (100 mg/m(2)), with carboplatin targeting an AUC of 4 mg x min/ml.