Phase I and pharmacokinetic study of sequential paclitaxel and trabectedin every 2 weeks in patients with advanced solid tumors.

PURPOSE This phase I study evaluated the feasibility, safety, pharmacokinetics (PK), and preliminary evidence of anticancer activity of the sequential administration of paclitaxel and trabectedin on an every-2-week schedule in patients with refractory solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) level on this schedule, as well as to recommend doses for disease-directed studies. EXPERIMENTAL DESIGN Twenty-seven patients were treated with paclitaxel (80-120 mg/m(2); 1-hour i.v. infusion, day 1) and trabectedin (0.525-0.775 mg/m(2); 3-hour i.v. infusion, day 2) with doses increased in successive cohorts. Blood sampling for PK and drug-drug interaction studies was done. RESULTS Neutropenia, which resulted in treatment delay exceeding 1 week, was the principal dose-limiting toxicity for this paclitaxel-trabectedin regimen and precluded dose escalation above 120 mg/m(2) paclitaxel and 0.650 mg/m(2) trabectedin. At the MTD (120 mg/m(2) paclitaxel and 0.650 mg/m(2) trabectedin), the safety profile was favorable in patients receiving cumulative treatment. Relevant drug-drug PK interactions between paclitaxel and trabectedin were not identified. A patient with soft tissue sarcoma had a complete response and several patients with various refractory solid malignancies showed protracted stable disease as their best response. CONCLUSIONS The MTD level of sequential paclitaxel 1-hour infusion (day 1) and trabectedin 3-hour infusion (day 2) administered every 2 weeks is 120 and 0.650 mg/m(2), respectively. The manageable toxicities at the MTD, preliminary evidence of antitumor activity, and lack of notable PK drug-drug interactions warrant further disease-directed studies of this regimen in relevant tumor types and settings.