A phase II trial of CPT-11 in patients (pts) with advanced gastric or gastroesophageal (GE) junction adenocarcinoma (ADCA): A clinical and pharmacodynamic evaluation. A North Central Cancer Treatment Group (NCCTG) Study.

4026 Background: The goals of this study were to determine the response rate (RR) and toxicity of CPT-11 as first-line therapy for gastric and GE junction ADCA, to describe the overall survival (OS) and time to progression (TTP), and to evaluate molecular markers as predictors of RR.,CPT-11 (320 mg/m IV) was given to 11 pts q3 weeks but was reduced to 290 mg/m and then to 260 mg/m, due to toxicity (JR Egner, et al. Proc Am Soc Clin Oncol, 18:282A, 1999). Pre-treatment tumor tissue was analyzed for DNA ploidy; and MIB-1, Bcl-2, p53, Bcl-xl, and Topoisomerase-I (TOPO) by immunohistochemistry. Ploidy, MIB-I, p53, and TOPO were quantified (% nuclear area) by digital image analysis (Sebo, et al. Am J Surg Pathol, 26(4):431-439, 2002).,Of 68 eligible patients entered on trial, 59 had pretreatment biopsies. A mean of 5 courses were administered (range 1-24). Grade 3+ toxicities included (% patients): neutropenia (41%), leukopenia (34%), diarrhea (21%), nausea (18%), vomiting (16%), lethargy (9%), and abdominal pain (7%). 13 confirmed responses (5 PR, 8 regressions) were observed (19%, 95% CI:12-33), with a median duration of 6 months (mos) (95% CI:4-8). Median TTP and OS were 3 mos (95% CI: 2-4) and 6 mos (95% CI:4-9). Pre-treatment biopsies revealed that 88.9% were nondiploid, 96.5% had weak or no staining for Bcl-2 and 83.9% had moderate to strong staining for Bcl-xl. MIB-1 and TOPO were positively correlated (rho=0.43, p<0.01). Only MIB-1 was significantly associated with RR (mean expression of 33.7% for responders versus 19.8% for nonresponders p<0.01).,CPT-11 alone in patients with gastric or GE junction ADCA showed modest activity. MIB-1 is a predictor for RR to CPT-11. Other biomarkers failed to demonstrate any association with outcome. (Supported in part by CA25224, CA73709, and Pharmacia & Upjohn) [Table: see text].