Phase I study of the safety and pharmacokinetics of trabectedin with docetaxel in patients with advanced malignancies.

Purpose: Combination therapy with trabectedin and docetaxel was evaluated in patients with advanced malignancies.

Methods: In this open-label phase 1 study, docetaxel (60 or 75 mg/m(2); 1-h intravenous infusion) was given on day 1 of a 21-day cycle in combination with escalating doses of trabectedin (0.4-1.3 mg/m(2) by 3-h intravenous infusion, 1 h after docetaxel) and prophylactic granulocyte colony-stimulating factor (G-CSF). Maximum tolerated dose (MTD) as primary objective and safety, plasma pharmacokinetics, and antitumor activity as secondary objectives were assessed.

Results: Patients (N = 49) received a median of four cycles of treatment. MTD was 1.3 mg/m(2) trabectedin and 60 mg/m(2) docetaxel for patients with limited and 1.1 mg/m(2) trabectedin and 60 mg/m(2) docetaxel for patients with unlimited prior chemotherapy. Dose-limiting toxicities (during cycle 1) included elevated alanine aminotransferase (ALT) and fatigue in patients with limited prior chemotherapy and elevated ALT and febrile neutropenia in those with unlimited prior chemotherapy. The most common drug-related adverse events were nausea (65 %), fatigue (63 %), and neutropenia (53 %). One patient achieved a complete response. Thirty patients had stable disease, and 11 had stable disease for ≥6 months. Pharmacokinetic results for trabectedin plus docetaxel were similar to those previously reported for the single agents.

Conclusion: In patients with previously treated, advanced malignancies, the combination of therapeutic doses of trabectedin and docetaxel showed clinical activity and was tolerable with prophylactic G-CSF, with no evidence of clinically important drug interactions.