A UGT1A1 *28 and *6 genotype-directed phase I study of irinotecan plus infusional leucovorin and 5-fluorouracil (sLV5FU2) in patients with previously untreated metastatic colorectal cancer (mCRC).

Abstract

3592 Background: We designed a phase I study to determine maximum tolerated dose (MTD) of irinotecan when combined with sLV5FU2 in mCRC patients (pts). Methods: Pts were genotyped for UGT1A1 *28 and *6, and stratified into 3 groups according to the number of defective allele (DA), designated 0 (*1/*1), 1 (*1/*28, *1/*6), and 2 (*28/*28, *6/*6, *6/*28). Within each group, the dose of irinotecan was escalated (table) in combination with fixed dose of sLV5FU2. Plasma drug levels and dose-limiting toxicity (DLT) were evaluated at cycle 1. Results: A total of 43 pts were accrued: 19 for 0 DA, 20 for 1 DA and 4 for 2 DA group. The MTD was estimated as 300 mg/m2/2-week for the 1 DA group with 2 DLTs in the level 3, and the MTD was not reached for the 0 DA group with 1 DLT in the level 4 (table). The mean relative extents of glucuronidation, AUClast ratio of SN-38G to SN-38, were 9.36, 6.81, and 5.09 for the 0, 1, and 2 DA groups, respectively (P=0.017). Of the 43 pts, five pts showed AUClast, SN38 that exceeded 400 ng·h/mL (1.02 umol·h/L) and DLT was observed in 40% (2/5). The overall response rate was 67.4% (95% CI, 51.5-80.9) with 6 complete responses and 23 partial responses. Median progression-free and overall survival was 8.0 months (95% CI, 7.1-8.9) and 25.6 months (95% CI, 23.4-27.7), respectively. Grade 3 or 4 toxicity during all treatment cycles included neutropenia (79% [0 DA]; 90% [1 DA]; 75% [2 DA]), leucopenia (21%; 30%; 0%), febrile neutropenia (0%; 10%; 0%) and diarrhea (0; 5%; 0) per patient. Conclusions: Dose-normalized exposure of SN38 was significantly higher in the 2 DA UGT1A1 group. Higher doses of irinotecan based on UGT1A1 genotyping are feasible when combined with sLV5FU2 in mCRC pts. The recommended dose of irinotecan was 330, 270, 150 mg/m2/2-week for pts with 0, 1, 2 DA based on pharmacokinetic analysis. [Table: see text]