Phase i combination study of trabectedin and capecitabine in patients with advanced malignancies

Summary: Background To determine the maximum tolerated dose (MTD), safety and pharmacokinetics of trabectedin with capecitabine in patients with advanced malignancies. Design In this Phase I, open-label, dose-finding study, patients refractory to standard therapy received trabectedin (3-h intravenous infusion, 0.4-1.3 mg/m², day 1) and capecitabine (2,000 or 1,600 mg/m ²/day orally, days 2-15) every 3 weeks. Standard 3+3 dose escalation was used to define the MTD. Antitumor response was assessed every two cycles; adverse events (AEs) were recorded throughout. Results Forty patients received 149 cycles of treatment (median 2; range 1-11) at nine dose levels. Gastrointestinal dose-limiting toxicities in two patients at two dose levels with capecitabine at 2,000 mg/m²/day prompted dose reduction to 1,600 mg/m²/day and initiation of new trabectedin dose escalation at 0.6 mg/m². The MTD was capecitabine 1,600 mg/m²/day + trabectedin 1.1 mg/m². Common grade 3-4 drug-related AEs were neutropenia (20%), nausea (18%), diarrhea (15%) and palmar-plantar erythrodysesthesia (15%). One patient with cholangiocarcinoma achieved a sustained partial response, and 18 patients maintained stable disease (six for ≥6 months). Conclusions The combination of trabectedin and capecitabine is generally well tolerated, without pharmacokinetic interactions, and shows some activity in patients with advanced cancers.