A Phase I and Pharmacokinetic Study of OSI-7904L, a Liposomal Thymidylate Synthase Inhibitor in Combination with Oxaliplatin in Patients with Advanced Colorectal Cancer.

A.R. Clamp, P. Schöffski, J.W. Valle, Richard Wilson, S. Marreaud, S- Govaerts, M. Debois, D. Lacombe, C. Twelves, J. Chick, G.C. Jayson

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15 Citations (Scopus)

Abstract

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/m(2), oxaliplatin 130 mg/m(2)) 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/m(2) and oxaliplatin 130 mg/m(2).
Original languageEnglish
Pages (from-to)579-585
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume61 (4)
Issue number4
DOIs
Publication statusPublished - Apr 2008

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

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    Clamp, A. R., Schöffski, P., Valle, J. W., Wilson, R., Marreaud, S., Govaerts, S., Debois, M., Lacombe, D., Twelves, C., Chick, J., & Jayson, G. C. (2008). A Phase I and Pharmacokinetic Study of OSI-7904L, a Liposomal Thymidylate Synthase Inhibitor in Combination with Oxaliplatin in Patients with Advanced Colorectal Cancer. Cancer Chemotherapy and Pharmacology, 61 (4)(4), 579-585. https://doi.org/10.1007/s00280-007-0509-5