Background: Infusional fluorouracil/leucovorin plus irinotecan with bevacizumab (FOLFIRI-bev) is a standard first-line option for mCRC. The active metabolite of irinotecan, SN-38, is inactivated via glucuronidation by UGT1A1. Common germline variants of UGT1A1 are well known to alter the rate of glucuronidation and exposure to SN-38. UGT1A1*28 decreases UGT1A1 expression such that *28/*28 homozygotes have greater SN-38 exposure and increased risk of neutropenia. Despite the well-described association of genotype and SN-38 exposure, irinotecan doses have been established independent of genotype. Dose-limiting toxicity in the ~10% of patients homozygous for *28/*28 may have led to under-dosing of patients with other genotypes. In phase I genotype-directed dose-finding studies of FOLFIRI +/- bev, *1/*1 and *1/*28 patients were able to tolerate significantly higher doses of irinotecan (Sharma GI ASCO 2014, Marcuello BJC 2011, Toffoli JCO 2010) with a promising efficacy signal. We hypothesize that genotype-guided irinotecan dosing—in which *1/*28 and *1/*1 genotypes receive higher doses of irinotecan—will increase the overall benefit of FOLFIRI-bev for patients with mCRC with tolerable toxicity. GENIC is a phase II multicenter, single arm trial designed to estimate the progression-free survival (PFS) of genotype-guided irinotecan dosing in patients receiving first-line FOLFIRI-bev for mCRC (NCT02138617). Methods: Patients with unresectable mCRC eligible for FOLFIRI-bev will be assigned irinotecan dose based on UGT1A1 genotype: *1/*1 = 310mg/m²; *1/*28 = 260mg/m²; or *28/*28 = 180mg/m². Fluorouracil, leucovorin, and bevacizumab are given at standard doses. The primary objective is to estimate PFS compared with recently reported PFS from FIRE-3 and 80405. 100 patients are planned to ensure 86 are evaluable, giving 80% power to detect a 3.5 month improvement in PFS. Secondary objectives will evaluate toxicity, response rate, and overall survival. Efficacy by genotype will be explored. The Patient Reported Outcomes (PRO) version of the CTCAE will evaluate patient reported tolerance and the concordance between patient and clinician assessment. Clinical trial information: NCT02138617