A phase I trial and pharmacokinetic study of aflibercept (VEGF Trap) in children with refractory solid tumors: A Children's Oncology Group Phase I Consortium Report
Clinical Cancer Research,
Bender JG et al. – The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower that the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of anti-tumor activity, but were dose-limiting.Methods
- Cohorts of 3-6 children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5 or 3.0 mg/kg/dose.
- PK sampling and analysis of peripheral blood biomarkers were performed with the initial dose.
- 21 eligible patients were enrolled; 18 were fully evaluable for toxicity.
- One of 6 patients receiving 2.0 mg/kg/dose developed dose-limiting intra-tumoral hemorrhage and 2 of 6 receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis.
- None of the 6 patients receiving 2.5 mg/kg/dose developed DLT, defining this as the MTD.
- The most common non-dose limiting toxicities were hypertension and fatigue.
- Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks.
- At the MTD, the ratio of free to bound aflibercept serum concentration was 2.10 on day 8, but only 0.44 by day 15.
- A rapid decrease in VEGF (p<0.05) and increase in PlGF (p<0.05) from baseline was observed in response to aflibercept by day 2.