Clinical assessment of 5-fluorouracil/leucovorin, nab-paclitaxel, and irinotecan (folfirabrax) in untreated patients with gastrointestinal cancer using UGT1A1 genotype–guided dosing

Smita S. Joshi, Daniel V.T. Catenacci, Theodore G. Karrison, Jaclyn D. Peterson, Mark M. Zalupski, Amikar Sehdev, James Wade, Ahad Sadiq, Vincent J. Picozzi, Andrea Amico, Robert Marsh, Mark F. Kozloff, Blase N. Polite, Hedy L. Kindler, Manish R. Sharma

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)18-24
Number of pages7
JournalClinical Cancer Research
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Joshi, S. S., Catenacci, D. V. T., Karrison, T. G., Peterson, J. D., Zalupski, M. M., Sehdev, A., Wade, J., Sadiq, A., Picozzi, V. J., Amico, A., Marsh, R., Kozloff, M. F., Polite, B. N., Kindler, H. L., & Sharma, M. R. (2020). Clinical assessment of 5-fluorouracil/leucovorin, nab-paclitaxel, and irinotecan (folfirabrax) in untreated patients with gastrointestinal cancer using UGT1A1 genotype–guided dosing. Clinical Cancer Research, 26(1), 18-24. https://doi.org/10.1158/1078-0432.CCR-19-1483