Dose-escalating and pharmacokinetic study of a weekly combination of paclitaxel and carboplatin for inoperable non-small cell lung cancer: JCOG 9910-DI

Objective: Combined paclitaxel and carboplatin is a standard regimen for inoperable non-small cell lung cancer (NSCLC). Although an every-3-week schedule is common, weekly paclitaxel is clinically effective for various cancers. A Phase I clinical trial was conducted to determine maximum-tolerated doses (MTDs) for weekly combined paclitaxel and carboplatin, and to evaluate anti-tumor response, toxicity and pharmacokinetics of paclitaxel in patients with inoperable NSCLC. Methods: Twenty patients with inoperable NSCLC received weekly carboplatin at area under the curve (AUC) = 2 mg/ml min and paclitaxel. Paclitaxel was escalated if MTD was not reached. Three patients each were entered at levels 1 and 2 (level 1, paclitaxel 50 mg/m² and carboplatin AUC = 2 mg/ml min; level 2, 60/2), six at level 3 (70/ 2), five at level 4 (80/2) and three at level 5 (90/2). Results: One patient had grade 4 (G4) neutropenia at level 2, one had G3 hepatic toxicity at level 3 and one had G3 cardiac toxicity at level 4. MTD was not reached for all dose levels. Response rate (RR) was 35% (7/ 20) and median survival was 11.1 months. Severe neutropenia (G3 and G4) was seen in seven patients associated with greater AUC, peak concentration (C_max) and the duration of plasma concentration >50 ng/ml of paclitaxel. Conclusions: Weekly combined paclitaxel (up to 90 mg/m²) and carboplatin (AUC = 2 mg/ml min) was well tolerated. A higher dose intensity of paclitaxel can be given, and RR and survival are not less than the every-3-week protocol. The weekly regimen is an alternative for untreated inoperable NSCLC patients.