GENOCARE: A Prospective, Randomized Clinical Trial of Genotype-Guided Dosing Versus Usual Care

This is a prospective, randomized study designed to compare genotype-guided dosing to usual care in patientswith any stage pancreas cancer and stage III-IV colorectal cancer who are UGT1A1 intermediate metabolizers andusual/extensive UGT metabolizers. All patients will be assessed for UGT1A1 genotype at screening and those withintermediate or usual/extensive UGT1A1 genotypes will be randomized to genotype-guided dosing versus usualcare. Genotype-guided dosing is defined in this study as an upfront dose reduction of 33% for irinotecan withsubsequent escalation to standard dose if no grade III-IV adverse effects are experienced by the patient after 2cycles for patients with an intermediate genotype and standard dose irinotecan for the extensive genotype. Usualcare is defined as irinotecan dosing without knowledge of genotype. Since there are standard dosingrecommendations for individuals with or poor metabolizer genotypes, these individuals will not be randomized andtheir genotype will be provided to the treating physician who will determine dosing on a case by case basis.Patients must have histologically or cytologically confirmed stage III-IV colorectal cancer or any stage pancreascancer and are planned to undergo treatment for their cancer and have not received prior irinotecan. The primaryaim is to compare the rate of adverse effects in UGT intermediate and UGT extensive/usual between genotype-guided dosing and usual care. Secondary aims include overall survival, time on treatment, clinical utility ofgenotyping, dose intensity, and association of SN-38 plasma concentrations with UGT1A1 genotype(PK samplingis only collected among Markey participants), and DPYD genotype (only collected among Markey participants).Clinical utility is defined as use of genotyping data to guide dosing in the observation cohort. Based on afrequency of UGT poor metabolizers of 10% and a 10% drop-out rate prior to randomization, we plan to genotype178 individuals to obtain a sample size of 72 in the usual care and 72 in the genotyping guided group.