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 À2 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 0 -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.

Phase I, Pharmacokinetic and Biological Correlative Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor, and Cisplatin in Patients with Solid Tumors

“…However, the overall median (range) t 1/2 in this study for OSI-7904L of 53.6 (33.1-90.4) h is similar to the 53.7 (7.63-135) h in the study reported by Falk et al, in which OSI-7904L was administered as a single agent at 12 mg/m 2 . Also, the median (range) plasma clearance of 121 (65.2-218) mL/h/m 2 (n = 4) for the 12 mg/m 2 group in our study is similar to the 98.8 (31.3-1244) mL/h/m 2 plasma clearance (n = 48) observed by Falk et al (15). These data suggest prior administration of CDDP has little effect on OSI-7904L pharmacokinetics.…”

“…Patient numbers were limited in this study and the majority had homocysteine levels within normal limits. In contrast to pemetrexed, data from this and other studies of OSI-7904L suggest that baseline homocysteine is not a predictive factor in identifying those patients at risk of severe toxicity (15). The number of patients in whom TS genotyping was done was too small to assess the potential effect of TS genotype on outcome with CDDP/OSI-7904L, but the collection and assessment of the promoter polymorphism via a single blood sample seem to be feasible in a prospective phase I setting.…”

“…In vivo pharmacokinetic data indicated that the liposomal formulation alters the disposition of the parent drug resulting in a prolonged plasma residence time (14). A phase II study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal cancer reported a response rate of 17%, with a similar toxicity profile to the phase I evaluation (15).…”

“…Aside from fatigue, severe nonhematologic and hematologic toxicity were uncommon at this dose level. Due to the appearance of grade 3 fatigue as a DLT at 9 mg/m 2 , dose escalation of OSI-7904L was discontinued; instead, CDDP was Noteworthy is that although skin-related toxicity occurred across most dose cohorts, this was at a lower incidence than that seen with single-agent studies of OSI-7904L (14,15). The lower incidence might be attributed to the prophylactic effects of dexamethasone routinely administered as part of the antiemetic premedication regimen for CDDP as well as the fact that OSI-7904L was dosed below 9.0 mg/m 2 in the majority of patients (15).…”

“…The activity of OSI-7904L monotherapy has been evaluated in patients with adenocarcinoma of the stomach or gastroesophageal junction (15). CDDP is among the most active agents used to treat this malignancy, and this feasibility study of OSI-7904L combined with CDDP is a logical step in the clinical development of OSI-7904L, particularly in light of potential synergy suggested by preclinical studies.…”