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dc.contributor.authorClamp, Andrew R
dc.contributor.authorSchöffski, Patrick
dc.contributor.authorValle, Juan W
dc.contributor.authorWilson, R
dc.contributor.authorMarreaud, Sandrine
dc.contributor.authorGovaerts, A-S
dc.contributor.authorDebois, M
dc.contributor.authorLacombe, D
dc.contributor.authorTwelves, C
dc.contributor.authorChick, J
dc.contributor.authorJayson, Gordon C
dc.date.accessioned2009-03-17T17:08:47Z
dc.date.available2009-03-17T17:08:47Z
dc.date.issued2008-04
dc.identifier.citationA 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.en
dc.identifier.issn0344-5704
dc.identifier.pmid17520255
dc.identifier.doi10.1007/s00280-007-0509-5
dc.identifier.urihttp://hdl.handle.net/10541/56021
dc.description.abstractPURPOSE: 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).
dc.language.isoenen
dc.subjectPhase Ien
dc.subjectOSI-7904Len
dc.subjectOxaliplatinen
dc.subjectThymidylate Synthaseen
dc.subjectColorectal Carcinomaen
dc.subject.meshAged
dc.subject.meshAntineoplastic Agents
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols
dc.subject.meshColorectal Neoplasms
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshEnzyme Inhibitors
dc.subject.meshFemale
dc.subject.meshGlutarates
dc.subject.meshHumans
dc.subject.meshIsoindoles
dc.subject.meshLiposomes
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshOrganoplatinum Compounds
dc.subject.meshPharmacogenetics
dc.subject.meshPolymorphism, Genetic
dc.subject.meshQuinazolines
dc.subject.meshThymidylate Synthase
dc.titleA phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK and University of Manchester Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester, M20 4BX, UK. Andrew.Clamp@christie.nhs.uken
dc.identifier.journalCancer Chemotherapy and Pharmacologyen
html.description.abstractPURPOSE: 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).


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