A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer
| Autor: | Richard H. Wilson, Andrew R Clamp, Patrick Schöffski, Juan W. Valle, Sandrine Marreaud, Denis Lacombe, Gordon C Jayson, J. Chick, M Debois, AS Govaerts, C Twelves |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Organoplatinum Compounds medicine.medical_treatment Antineoplastic Agents Isoindoles Toxicology Gastroenterology Thymidylate synthase Glutarates Thymidylate synthase inhibitor Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Mucositis Humans Pharmacology (medical) Enzyme Inhibitors Aged Pharmacology Chemotherapy Polymorphism Genetic Dose-Response Relationship Drug biology business.industry Thymidylate Synthase Middle Aged medicine.disease Oxaliplatin Regimen Oncology Tolerability Pharmacogenetics Fluorouracil Liposomes Immunology Quinazolines biology.protein Female Colorectal Neoplasms business medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 61:579-585 |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-007-0509-5 |
| Popis: | 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.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.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.The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2). |
| Databáze: | OpenAIRE |
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