Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer.

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. Clin Cancer Res; 23(4); 918-24. ©2016 AACR.

• Authors: Giuseppe Toffoli, Manish R Sharma, Elena Marangon, Bianca Posocco, Elizabeth Gray, Quan Mai, Angela Buonadonna, Blase N Polite, Gianmaria Miolo, Gianna Tabaro, Federico Innocenti
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 4 Pg. 918-924 (Feb 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 27507617 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Bevacizumab
• Irinotecan
• UGT1A1 enzyme
• Glucuronosyltransferase
• Leucovorin
• Fluorouracil
• Camptothecin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Bevacizumab (administration & dosage, adverse effects)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives)
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Female
• Fluorouracil (administration & dosage, adverse effects)
• Genotype
• Glucuronosyltransferase (genetics)
• Humans
• Irinotecan
• Leucovorin (administration & dosage, adverse effects)
• Male
• Middle Aged
• Neoplasm Metastasis