A Phase I Study of UGT1A1 *28/*6 Genotype-Directed Dosing of Irinotecan (CPT-11) in Korean Patients with Metastatic Colorectal Cancer Receiving FOLFIRI.

Purpose: A UGT1A1 genotype-directed dose escalation of irinotecan (CPT-11) was performed in patients with metastatic colorectal cancer receiving first-line FOLFIRI chemotherapy. Methods: Patients were genotyped for UGT1A1 and stratified according to the number of defective alleles (DA; *28 and *6). The irinotecan dose was escalated with a fixed dose of 5-fluorouracil and leucovorin in a standard 3 + 3 design. Results: In 43 enrolled patients, the maximum tolerated dose (MTD) was 300 mg/m² for the 1 DA group, while the MTD was not reached for the 0 DA group with 1 dose-limiting toxicity (DLT) at 330 mg/m² and for the 2 DA group with 0 DLT at 150 mg/m². Because of the risk of being exposed to unsafe doses, the trial was terminated before the MTD was reached in the 0 DA and 2 DA groups. The recommended doses were 300 (0 DA), 270 (1 DA) and 150 (0 DA) mg/m². The 2 DA group displayed 27% lower SN-38 exposure levels relative to the 0 and 1 DA groups (95% CI, 0.47-1.15). Conclusions: The MTD of irinotecan differed according to the UGT1A1 genotype, and higher doses of irinotecan are feasible with sLV5FU2 compared to the present regulatory approved doses. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]