Genotype-Directed Study Of Irinotecan Dosing In FOLFIRI + BevacizumabTreated Metastatic Colorectal Cancer

Summary

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Description

This phase II multicenter clinical trial will use a genotype-guided dosing strategy for irinotecan to prospectively analyze efficacy in 100 metastatic colorectal cancer patients (mCRC) receiving FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) plus bevacizumab. Irinotecan is detoxified and ex...

This phase II multicenter clinical trial will use a genotype-guided dosing strategy for irinotecan to prospectively analyze efficacy in 100 metastatic colorectal cancer patients (mCRC) receiving FOLFIRI (5-fluorouracil (5-FU), leucovorin, irinotecan) plus bevacizumab. Irinotecan is detoxified and excreted primarily by glucuronidation in the liver via the isoenzyme uridine diphosphate glucuronosyl transferase (UGT1A1). Common variants in UGT1A1 alter the rate of glucuronidation and thus alter exposure to irinotecan. The UGT1A1 *28 allele results in slower irinotecan glucuronidation, and thus greater exposure to its active metabolite SN-38. At the standard irinotecan dose used in FOLFIRI (180 mg/m2; established prior to our understanding of the importance of genotype in the rate of this drug's metabolism), there is a small increased risk of neutropenia in *28 homozygotes. However, the risk of clinically important consequences of neutropenia, such as febrile neutropenia and infection, are not significantly increased. Patients with other genotypes have a quite low risk of adverse effects suggesting patients with these low risk genotypes may tolerate higher doses of irinotecan in FOLFIRI. This finding was demonstrated in a phase I study in which *1/*28 and *1/*1 genotypes were able to tolerate escalating doses of irinotecan up to 260 mg/m2 and 310 mg/m2, respectively. The central hypothesis of this trial is that increasing the irinotecan dose in *1/*28 and *1/*1 genotypes will increase the overall benefit of FOLFIRI for patients with mCRC as these two groups are likely under-dosed with the current dosing regimen. Eligible patients will be genotyped for UGT1A1 and assigned into 1 of 3 different dosing groups, based on their relative rate of metabolism. The primary objective of this trial is to estimate progression-free survival (PFS), and secondary objectives include characterization of toxicity and objective response rate (OR; complete response (CR) + partial response (PR)).

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