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dc.contributor.authorFalk, Stephen J
dc.contributor.authorAnthoney, A
dc.contributor.authorEatock, Martin M
dc.contributor.authorVan Cutsem, E
dc.contributor.authorChick, J
dc.contributor.authorGlen, H
dc.contributor.authorValle, Juan W
dc.contributor.authorDrolet, D W
dc.contributor.authorAlbert, D
dc.contributor.authorFerry, David R
dc.contributor.authorAjani, J
dc.date.accessioned2009-07-02T16:03:10Z
dc.date.available2009-07-02T16:03:10Z
dc.date.issued2006-08-21
dc.identifier.citationMulticentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma. 2006, 95 (4):450-6 Br. J. Canceren
dc.identifier.issn0007-0920
dc.identifier.pmid16880795
dc.identifier.doi10.1038/sj.bjc.6603267
dc.identifier.urihttp://hdl.handle.net/10541/72333
dc.description.abstractA two-stage Simon design was used to evaluate the response rate of OSI-7904L, a liposome encapsulated thymidylate synthase inhibitor, in advanced gastric and/or gastroesophageal adenocarcinoma (A-G/GEJA), administered intravenously at 12 mg m(-2) over 30 min every 21 days. Fifty patients were treated. Median age was 64 years (range 35-82), 62% were male and 89% had ECOG PS of 0/1. A total of 252 cycles were administered; median of 4 per patient (range 1-21). Twelve patients required dose reductions, mainly for skin toxicity. Investigator assessed response rate was 17.4% (95% CI 7.8-31.4) with one complete and seven partial responses in 46 evaluable patients. Twenty-one patients (42%) had stable disease. Median time to progression and survival were 12.4 and 36.9 weeks, respectively. NCI CTCAE Grade 3/4 neutropenia (14%) and thrombocytopenia (4%) were uncommon. The main G3/4 nonhaematological toxicities were skin-related 22%, stomatitis 14%, fatigue/lethargy 10%, and diarrhea 8%. Pharmacokinetic data showed high interpatient variability. Patients with higher AUC were more likely to experience G3/4 toxicity during cycle 1 while baseline homocysteine did not predict toxicity. Response did not correlate with AUC. Elevations in 2'-dU were observed indicating target inhibition. Analysis of TS genotype, TS protein and expression did not reveal any correlation with outcome. OSI-7904L has activity in A-G/GEJA similar to other active agents and an acceptable safety profile.
dc.language.isoenen
dc.subjectOesophageal Canceren
dc.subjectStomach Canceren
dc.subjectOesophagogastric Junctionen
dc.subject.meshAdenocarcinoma
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshAged, 80 and over
dc.subject.meshAntineoplastic Agents
dc.subject.meshEsophageal Neoplasms
dc.subject.meshEsophagogastric Junction
dc.subject.meshFemale
dc.subject.meshGlutarates
dc.subject.meshHumans
dc.subject.meshIsoindoles
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshQuinazolines
dc.subject.meshStomach Neoplasms
dc.subject.meshSurvival Analysis
dc.subject.meshTreatment Outcome
dc.titleMulticentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma.en
dc.typeArticleen
dc.contributor.departmentBristol Haematology and Oncology Centre, Horfield Road, Bristol BS2 8ED, UK. Stephen.Falk@ubht.nhs.uken
dc.identifier.journalBritish Journal of Canceren
html.description.abstractA two-stage Simon design was used to evaluate the response rate of OSI-7904L, a liposome encapsulated thymidylate synthase inhibitor, in advanced gastric and/or gastroesophageal adenocarcinoma (A-G/GEJA), administered intravenously at 12 mg m(-2) over 30 min every 21 days. Fifty patients were treated. Median age was 64 years (range 35-82), 62% were male and 89% had ECOG PS of 0/1. A total of 252 cycles were administered; median of 4 per patient (range 1-21). Twelve patients required dose reductions, mainly for skin toxicity. Investigator assessed response rate was 17.4% (95% CI 7.8-31.4) with one complete and seven partial responses in 46 evaluable patients. Twenty-one patients (42%) had stable disease. Median time to progression and survival were 12.4 and 36.9 weeks, respectively. NCI CTCAE Grade 3/4 neutropenia (14%) and thrombocytopenia (4%) were uncommon. The main G3/4 nonhaematological toxicities were skin-related 22%, stomatitis 14%, fatigue/lethargy 10%, and diarrhea 8%. Pharmacokinetic data showed high interpatient variability. Patients with higher AUC were more likely to experience G3/4 toxicity during cycle 1 while baseline homocysteine did not predict toxicity. Response did not correlate with AUC. Elevations in 2'-dU were observed indicating target inhibition. Analysis of TS genotype, TS protein and expression did not reveal any correlation with outcome. OSI-7904L has activity in A-G/GEJA similar to other active agents and an acceptable safety profile.


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