A Phase I and Pharmacokinetic Study of Weekly Paclitaxel and Carboplatin in Patients with Metastatic Esophageal Cancer

Abstract

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/m2 followed by a 1-h infusion of carboplatin targeting an area under the curve (AUC) of 2-5 mg × 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 × 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 × min/ml. The mean (±SD) AUCs of unbound (Cu) and total paclitaxel were 0.662 ± 0.186 and 7.37 ± 1.33 μM × h, respectively. Clearance of Cu was 188 ± 44.6 liter/h/m2, which is not significantly different from historical data (P = 0.52). Cremophor EL clearance was 123 ± 23 ml/h/m2, 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/m2), with carboplatin targeting an AUC of 4 mg × min/ml.