Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma.
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.
Falk
S
S
Bristol Haematology and Oncology Centre, Horfield Road, Bristol BS2 8ED, UK. Stephen.Falk@ubht.nhs.uk
Anthoney
A
A
Eatock
M
M
Van Cutsem
E
E
Chick
J
J
Glen
H
H
Valle
J W
JW
Drolet
D W
DW
Albert
D
D
Ferry
D
D
Ajani
J
J
D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D004943:Esophagogastric Junction; D005260:Female; D005977:Glutarates / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D054833:Isoindoles; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D016019:Survival Analysis; D016896:Treatment Outcome
C506644:((S)-2-(5-(1,2-dihydro-3-methyl-1-oxobenzo(f)-quinazoline-9-yl)methyl)amino-1-oxo-2-isoindolynyl)-glutaric acid; D000970:Antineoplastic Agents; D005977:Glutarates; D054833:Isoindoles; D011799:Quinazolines