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)

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Abstract

Background

We designed a phase I study to determine a maximum tolerated dose (MTD) of irinotecan when combined with sLV5FU2 in mCRC patients.

Methods

Patients were genotyped for UGT1A1*28 and *6, and stratified into three 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 patients 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 one DA group with two DLTs in that dose level, and the MTD was not reached for the 0 DA group with 1 DLT at 330 mg/m2/2 week. For the two DA patients, dose was not elevated above the recommended dose of 150 mg/m2/2 week despite no DLTs. 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 patients, 5 showed AUClast, SN38 that exceeded 400 ng h/ml (1.02 µmol 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 two DA UGT1A1 group. Higher doses of irinotecan based on UGT1A1 genotyping are feasible when combined with sLV5FU2 in mCRC patients. The recommended dose of irinotecan was 330, 270, 150 mg/m2/2 week for patients with 0, 1, 2 DA based on pharmacokinetic analysis.

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