Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma.

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.

• Authors: S Falk, A Anthoney, M Eatock, E Van Cutsem, J Chick, H Glen, J W Valle, D W Drolet, D Albert, D Ferry, J Ajani
• Journal: British journal of cancer (Br J Cancer) Vol. 95 Issue 4 Pg. 450-6 (Aug 21 2006) ISSN: 0007-0920 [Print] England
• PMID: 16880795 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• ((S)-2-(5-(1,2-dihydro-3-methyl-1-oxobenzo(f)-quinazoline-9-yl)methyl)amino-1-oxo-2-isoindolynyl)-glutaric acid
• Antineoplastic Agents
• Glutarates
• Isoindoles
• Quinazolines

Topics

• Adenocarcinoma
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents
• Esophageal Neoplasms (drug therapy, metabolism)
• Esophagogastric Junction
• Female
• Glutarates (adverse effects, therapeutic use)
• Humans
• Isoindoles
• Male
• Middle Aged
• Quinazolines (adverse effects, therapeutic use)
• Stomach Neoplasms (drug therapy, metabolism)
• Survival Analysis
• Treatment Outcome