A phase I study of intravenous aflibercept with FOLFIRI in Japanese patients with previously treated metastatic colorectal cancer

Abstract

Aflibercept, a recombinant fusion protein, is a potent inhibitor of vascular endothelial growth factor (VEGF)-A, VEGF-B, and the placental growth factor (PlGF). The present study was an open-label, sequential-cohort, dose-escalation trial of intravenous aflibercept administered every 2 weeks in combination with 5-fluorouracil, levofolinate, and irinotecan (FOLFIRI) in patients with previously treated metastatic colorectal cancer (mCRC). We aimed to assess the safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary efficacy of the combination therapy to determine the recommended phase II dose (RPTD) for Japanese patients. Two doses of aflibercept (2.0 and 4.0 mg/kg) were set, and DLTs were evaluated in the first 2 cycles. The subjects comprised 16 patients (n = 3 and 13 for 2.0 and 4.0 mg/kg aflibercept, respectively) who received a total of 149 cycles of aflibercept with FOLFIRI. No DLTs were observed at both doses. The frequent adverse events encountered were leukopenia, neutropenia, anemia, diarrhea, fatigue, decreased appetite, stomatitis, dysphonia, nausea, and epistaxis. The most common grade 3/4 adverse events were neutropenia for both doses and hypertension for the 4.0 mg/kg dose. Free aflibercept exposure increased with the dose, whereas exposure to VEGF-bound aflibercept remained similar at both doses. The response rate and progression-free survival at 4.0 mg/kg was 8.3 % and 7.59 months, respectively. In conclusion, the combination of aflibercept and FOLFIRI was well tolerated at both doses. The RPTD of aflibercept in combination with FOLFIRI for Japanese patients with mCRC was determined to be 4.0 mg/kg every 2 weeks. ClinicalTrials.gov identifier: NCT00921661.

Figures

Fig. 1

Mean plasma concentration versus time profiles of free and VEGF-bound aflibercept (log scale) for cycle 1. After aflibercept infusion, the plasma concentration of free aflibercept decreased, whereas that of VEGF-bound aflibercept gradually increased throughout the 2-week cycle. The plasma concentration of free aflibercept increased with the dose, whereas that of VEGF-bound aflibercept was similar at both doses

Fig. 2

Ratio of free aflibercept concentration to VEGF-bound aflibercept concentration at the trough (2 weeks after aflibercept administration) across the treatment cycles for dose 2 (4.0 mg/kg). The mean ± SD value for each cycle is indicated. Note that the free/VEGF-bound aflibercept concentration ratio was maintained at >1 (dotted line) throughout the treatment duration