Phase I study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor in patients with refractory solid tumors.

Purpose: OSI-7904L is a liposomal formulation of a potent noncompetitive thymidylate synthase inhibitor (TSI) that does not require polyglutamation for activity. This phase I study was done to establish the safety, tolerability, maximum tolerated dose, recommended dose, and pharmacokinetics of OSI-7904L in patients with advanced solid tumors refractory to standard therapy.

Design: OSI-7904L was given as a 30-minute i.v. infusion every 21 days to 31 patients at eight dose levels from 0.4 to 15.0 mg/m(2), using three patients per dose level, up to 10 patients at the recommended dose. Baseline plasma homocysteine and 2'-deoxyuridine and genotype polymorphism were measured as potential predictors of biological activity.

Results: Minimal toxicity was reported up to 9.6 mg/m(2), but dose-limiting toxicity was seen in both patients at 15 mg/m(2) including stomatitis, fatigue, tachyarrhythmia, rash and hand-foot syndrome, diarrhea, and fatal neutropenic sepsis. Other toxicity such as nausea and vomiting was mild or moderate. This resulted in the investigation of an intermediate dose level of 12 mg/m(2), identified as the recommended dose for phase II studies. Prolonged disease stabilization was reported in 11 of 31 heavily pretreated patients. Pharmacokinetic data indicate that this liposomal formulation alters the disposition properties of the parent drug resulting in a prolonged plasma residence time.

Conclusions: OSI-7904L given as a 30-minute i.v. infusion every 21 days is feasible and well tolerated at the recommended phase II dose of 12 mg/m(2). The main toxicities are rash, pruritus, lethargy, stomatitis, and myelosuppression. Observed toxicities were predictable and characteristic for TSIs.