Phase I clinical and pharmacokinetic study of trabectedin and carboplatin in patients with advanced solid tumors

Purpose This study intended to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RD) of trabectedin combined with carboplatin in patients with advanced solid tumors. Patients and methods Carboplatin-pretreated patients received carboplatin AUC 4 (Group 1), whereas carboplatin-naïve patients received carboplatin AUC 5 (Group 2) as a 1-h i.v. infusion followed by trabectedin at dose range from 0.5–1.2 mg/m² in the schedule of 3-h/every-3-weeks. Pharmacokinetic (PK) sampling was performed in the first 2 cycles. Results Forty-four patients were treated and evaluable for safety and dose-limiting toxicities (DLTs). In Group 1, at trabectedin 1.0 mg/m², cumulative hematological toxicity was found in all patients and 1/10 patients had DLTs. The RD was considered trabectedin 0.8 mg/m² combined with carboplatin AUC 4. Although no DLT occurred at this dose level, frequent dose delays (28.6%) and the 4-week cycle re-scheduling (66.7%) were required. In Group 2, DLTs occurred at trabectedin 0.8 mg/m² (3/8 patients), 1.0 mg/m² (3/10 patients) and 1.2 mg/m² (2/2 patients) with cumulative hematological toxicity associated with an important number of transfusions. In this group, neither the MTD nor the RD were established. Promising antitumor activity was found for this carboplatin/trabectedin combination; especially in patients with advanced ovarian cancer and soft tissue sarcoma. No significant PK drug–drug interaction occurred. Conclusions This study established a trabectedin dose of 0.8 mg/m² combined with carboplatin AUC 4 and given every 4 weeks as the most feasible schedule in carboplatin-pretreated patients. Dose and cycle recommendations for carboplatin-naïve patients warrant further evaluation.