Three separate dose escalation studies have established that patients with UGT1A1 genotypes (*1/*1 and *1/*28) associated with lower risk of severe toxicity can be treated with doses of irinotecan that are significantly higher than the standard 180 mg/m2. Whether this leads to better efficacy has not been established. Because we hypothesize that a large proportion of patients currently treated with FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab receive suboptimal doses of irinotecan, we plan to conduct a novel phase II genotype-driven study of irinotecan in metastatic colorectal cancer (mCRC) patients receiving FOLFIRI plus bevacizumab. Eligible patients will be genotyped for the UGT1A1*28 allele and assigned a *1/*1, *1/*28, or *28/*28 genotype. As part of a biweekly regimen, patients will receive previously defined maximum tolerated doses of irinotecan stratified by genotype: 310 and 260 mg/m2 for *1/*1 and *1/*28 patients, respectively, while *28/*28 patients will receive the standard dose of 180 mg/m2. We plan to accrue 70 patients (accounting for dropouts) over a two-year period utilizing the UNC Cancer Network. The aims of the study are to: 1) evaluate the progression-free survival (PFS) in this patient population dosed according to UGT1A1 genotype, and 2) evaluate the toxicity profile. An estimated sample size of 63 is needed for 80% power to detect a clinically significant PFS improvement of 3.5 months over historical control (null median PFS and alternative median PFS of 9.5 and 13.0 months, respectively). If positive, this study will be instrumental to the design of a larger phase III randomized study.
PI: Federico Innocenti, MD, PhD
Department: UNC Eshelman School of Pharmacy