A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer

Purpose OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma. Method A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity. Results Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m², oxaliplatin 130 mg/m²) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients. Conclusions The recommended regimen for further investigation is OSI-7904L 9 mg/m² and oxaliplatin 130 mg/m².