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

Abstract

<b>Purpose:</b><i>UGT1A1*28</i> confers a higher risk of toxicity in patients treated with irinotecan. Patients with <i>*1/*1</i> and <i>*1/*28</i> 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 <i>*1/*1</i> and <i>*1/*28</i> genotypes treated with FOLFIRI plus bevacizumab, and to determine whether bevacizumab alters irinotecan pharmacokinetics.<b>Experimental Design:</b> Previously untreated patients with mCRC (25 <i>*1/*1</i>; 23 <i>*1/*28</i>) 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).<b>Results:</b> For <i>*1/*1</i> 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 <i>*1/*28</i> 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.<b>Conclusions:</b> The MTD of irinotecan in FOLFIRI plus bevacizumab is 310 mg/m² for <i>UGT1A1 *1/*1</i> patients and 260 mg/m² for <i>*1/*28</i> 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. <i>Clin Cancer Res; 23(4); 918-24. ©2016 AACR</i>.