Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma.
dc.contributor.author | Falk, Stephen J | |
dc.contributor.author | Anthoney, A | |
dc.contributor.author | Eatock, Martin M | |
dc.contributor.author | Van Cutsem, E | |
dc.contributor.author | Chick, J | |
dc.contributor.author | Glen, H | |
dc.contributor.author | Valle, Juan W | |
dc.contributor.author | Drolet, D W | |
dc.contributor.author | Albert, D | |
dc.contributor.author | Ferry, David R | |
dc.contributor.author | Ajani, J | |
dc.date.accessioned | 2009-07-02T16:03:10Z | |
dc.date.available | 2009-07-02T16:03:10Z | |
dc.date.issued | 2006-08-21 | |
dc.identifier.citation | Multicentre 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. Cancer | en |
dc.identifier.issn | 0007-0920 | |
dc.identifier.pmid | 16880795 | |
dc.identifier.doi | 10.1038/sj.bjc.6603267 | |
dc.identifier.uri | http://hdl.handle.net/10541/72333 | |
dc.description.abstract | A 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.iso | en | en |
dc.subject | Oesophageal Cancer | en |
dc.subject | Stomach Cancer | en |
dc.subject | Oesophagogastric Junction | en |
dc.subject.mesh | Adenocarcinoma | |
dc.subject.mesh | Adult | |
dc.subject.mesh | Aged | |
dc.subject.mesh | Aged, 80 and over | |
dc.subject.mesh | Antineoplastic Agents | |
dc.subject.mesh | Esophageal Neoplasms | |
dc.subject.mesh | Esophagogastric Junction | |
dc.subject.mesh | Female | |
dc.subject.mesh | Glutarates | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Isoindoles | |
dc.subject.mesh | Male | |
dc.subject.mesh | Middle Aged | |
dc.subject.mesh | Quinazolines | |
dc.subject.mesh | Stomach Neoplasms | |
dc.subject.mesh | Survival Analysis | |
dc.subject.mesh | Treatment Outcome | |
dc.title | Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma. | en |
dc.type | Article | en |
dc.contributor.department | Bristol Haematology and Oncology Centre, Horfield Road, Bristol BS2 8ED, UK. Stephen.Falk@ubht.nhs.uk | en |
dc.identifier.journal | British Journal of Cancer | en |
html.description.abstract | A 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. |