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

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    Authors
    Clamp, Andrew R
    Schöffski, Patrick
    Valle, Juan W
    Wilson, R
    Marreaud, Sandrine
    Govaerts, A-S
    Debois, M
    Lacombe, D
    Twelves, C
    Chick, J
    Jayson, Gordon C
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    Affiliation
    Cancer Research UK and University of Manchester Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester, M20 4BX, UK. Andrew.Clamp@christie.nhs.uk
    Issue Date
    2008-04
    
    Metadata
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    Abstract
    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/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).
    Citation
    A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer. 2008, 61 (4):579-85 Cancer Chemother. Pharmacol.
    Journal
    Cancer Chemotherapy and Pharmacology
    URI
    http://hdl.handle.net/10541/56021
    DOI
    10.1007/s00280-007-0509-5
    PubMed ID
    17520255
    Type
    Article
    Language
    en
    ISSN
    0344-5704
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00280-007-0509-5
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research
    Medical Oncology
    Medical Oncology

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