Clinical Assessment of 5-Fluorouracil/Leucovorin, Nab-Paclitaxel, and Irinotecan (FOLFIRABRAX) in Untreated Patients with Gastrointestinal Cancer Using <i>UGT1A1</i> Genotype-Guided Dosing.

Abstract

5-Fluorouracil (5-FU)/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. <i>UGT1A1*28</i> polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with <i>UGT1A1</i> genotype-guided dosing of irinotecan. Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. <i>UGT1A1 *1/*1, *1/*28</i>, and <i>*28/*28</i> patients received initial irinotecan doses of 180, 135, and 90 mg/m², respectively. 5-FU 2,400 mg/m² over 46 hours, leucovorin 400 mg/m², and nab-paclitaxel 125 mg/m² were administered. Doses were deemed tolerable if the dose-limiting toxicity (DLT) rate during cycle 1 was ≤35% in each genotype group. DLTs were monitored using a sequential procedure. Fifty patients enrolled, 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5 of 23 (22%) <i>*1/*1</i> patients, 1 of 19 (5%) <i>*1/*28</i> patients, and 0 of 7 <i>*28/*28</i> patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks. FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and <i>UGT1A1*1*1</i> or <i>UGT1A1*1*28</i> genotypes. Too few <i>*28/*28</i> patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.