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.
ASJC Scopus subject areas
- Cancer Research