title: Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer.
abstract: Purpose:UGT1A1*28confers a higher risk of toxicity in patients treated with irinotecan. Patients with*1/*1and*1/*28genotypes 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/*1and*1/*28genotypes 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/m2The 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/*1patients, 2 DLTs were observed among 10 patients at 310 mg/m2, while 370 mg/m2was not tolerated (2 DLTs in 4 patients). For*1/*28patients, 2 DLTs were observed among 10 patients at 260 mg/m2, while 310 mg/m2was 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/m2forUGT1A1 *1/*1patients and 260 mg/m2for*1/*28patients. 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: Centro di Riferimento Oncologico, Aviano, Italy. innocent@unc.edu gtoffoli@cro.it.
authors: Giuseppe
authors: G
authors: Toffoli
authors: University of Chicago, Chicago, Illinois.
authors: Manish R
authors: MR
authors: Sharma
authors: Centro di Riferimento Oncologico, Aviano, Italy.
authors: Elena
authors: E
authors: Marangon
authors: Centro di Riferimento Oncologico, Aviano, Italy.
authors: Bianca
authors: B
authors: Posocco
authors: NorthShore University Health System, Evanston, Illinois.
authors: Elizabeth
authors: E
authors: Gray
authors: Northwestern University, Chicago, Illinois.
authors: Quan
authors: Q
authors: Mai
authors: Centro di Riferimento Oncologico, Aviano, Italy.
authors: Angela
authors: A
authors: Buonadonna
authors: University of Chicago, Chicago, Illinois.
authors: Blase N
authors: BN
authors: Polite
authors: Centro di Riferimento Oncologico, Aviano, Italy.
authors: Gianmaria
authors: G
authors: Miolo
authors: Centro di Riferimento Oncologico, Aviano, Italy.
authors: Gianna
authors: G
authors: Tabaro
authors: University of North Carolina, Chapel Hill, North Carolina. innocent@unc.edu gtoffoli@cro.it.
authors: Federico
authors: F
authors: Innocenti
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000099148:UGT1A1 Enzyme
chemical_list: D000068258:Bevacizumab; D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D000099148:UGT1A1 Enzyme