Genotype-guided dosing study of FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer

Giuseppe Toffoli, Manish R. Sharma, Elena Marangon, Bianca Posocco, Elizabeth Gray, Quan Mai, Angela Buonadonna, Blase N. Polite, Gianmaria Miolo, Gianna Tabaro, Federico Innocenti

Research output: Contribution to journalArticle

Abstract

Purpose: UGT1A1∗28 confers a higher risk of toxicity in patients treated with irinotecan. Patients with ∗1/∗1 and ∗1/∗28 genotypes might tolerate higher than standard doses of irinotecan. We aimed to identify the MTD of irinotecan in patients with metastatic colorectal cancer (mCRC) with ∗1/∗1 and ∗1/∗28 genotypes treated with FOLFIRI plus bevacizumab, and to determine whether bevacizumab alters irinotecan pharmacokinetics. Experimental Design: Previously untreated patients with mCRC (25∗1/∗1;23∗1/∗28) were given FOLFIRI plus bevacizumab every 2 weeks. The irinotecan dose was escalated using a 3 + 3 design in each genotype group as follows: 260, 310, and 370 mg/m2. The MTD was the highest dose at which <4/10 patients had a dose-limiting toxicity (DLT). Pharmacokinetics of irinotecan and SN-38 were measured on days 1 to 3 (without bevacizumab) and 15 to 17 (with bevacizumab). Results: For ∗1/∗1 patients, 2 DLTs were observed among 10 patients at 310 mg/m2, while 370 mg/m2 was not tolerated (2 DLTs in 4 patients). For ∗1/∗28 patients, 2 DLTs were observed among 10 patients at 260 mg/m2, while 310 mg/m2 was not tolerated (4 DLTs in 10 patients). Neutropenia and diarrhea were the most common DLTs. Changes in the AUCs of irinotecan and SN-38 associated with bevacizumab treatment were marginal. Conclusions: The MTD of irinotecan in FOLFIRI plus bevacizumab is 310 mg/m2 for UGT1A1 ∗1/∗1 patients and 260 mg/m2 for ∗1/∗28 patients. Bevacizumab does not alter the pharmacokinetics of irinotecan. The antitumor efficacy of these genotype-guided doses should be tested in future studies of patients with mCRC treated with FOLFIRI plus bevacizumab.

Original languageEnglish
Pages (from-to)918-924
Number of pages7
JournalClinical Cancer Research
Volume23
Issue number4
DOIs
Publication statusPublished - Feb 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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