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Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer
- Source :
- Clinical Cancer Research. 23:918-924
- Publication Year :
- 2017
- Publisher :
- American Association for Cancer Research (AACR), 2017.
-
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 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.
- Subjects :
- Adult
Male
0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
Genotype
Bevacizumab
Colorectal cancer
Leucovorin
Neutropenia
Irinotecan
Disease-Free Survival
Article
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Dosing
Glucuronosyltransferase
Neoplasm Metastasis
Aged
Dose-Response Relationship, Drug
business.industry
Cancer
Middle Aged
medicine.disease
digestive system diseases
030104 developmental biology
030220 oncology & carcinogenesis
FOLFIRI
Camptothecin
Female
Fluorouracil
Colorectal Neoplasms
business
medicine.drug
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....8f49cf63ddc097b086c75c0576d0768c