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Clin Cancer Res ; 26(1): 18-24, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31558477

RESUMO

PURPOSE: 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. UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with UGT1A1 genotype-guided dosing of irinotecan. PATIENTS AND METHODS: Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. UGT1A1 *1/*1, *1/*28, and *28/*28 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. RESULTS: Fifty patients enrolled, 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5 of 23 (22%) *1/*1 patients, 1 of 19 (5%) *1/*28 patients, and 0 of 7 *28/*28 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. CONCLUSIONS: FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Too few *28/*28 patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Glucuronosiltransferase/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/patologia , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Segurança do Paciente , Resultado do Tratamento
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