Phase I/II pharmacokinetic and pharmacogenomic study of UGT1A1 polymorphism in elderly patients with advanced non-small cell lung cancer treated with irinotecan.

This phase II study investigated the recommended dose (RD) of irinotecan (CPT-11) by dose escalation in elderly (>or=70 years) chemotherapy-naive Japanese patients with advanced non-small cell lung cancer. UGT1A1*28 and *6 polymorphisms and pharmacokinetics were also investigated. Thirty-seven patients received the RD, 100 mg/m(2) of intravenous CPT-11, on days 1 and 8 of each 3-week cycle in phase II. The overall response rate was 8.1%. The median survival time was 441 days, and time to progression was 132 days. A significant correlation was observed between the incidence of grade 3/4 neutropenia and area under the time-concentration curve (AUC) values of SN-38. A reduction in AUC ratios (AUC(SN-38G)/AUC(SN-38)) and a rise in incidence of grade 3/4 neutropenia were observed with increase in polymorphism. The regimen was well tolerated and provided good disease control and promising survival effects. An analysis of the influence of UGT1A1*28 and *6 polymorphisms provides useful information for the prediction of CPT-11-related hematological toxicity.