A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors
Clinical Cancer Research, 08/09/2012
Bender JG et al. – The aflibercept maximum tolerated dose (MTD) in children of 2.5mg/kg/dose every 14days is lower than the adult recommended dose of 4.0mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose–limiting.Methods
- Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60minutes every 14days, at 2.0, 2.5, or 3.0mg/kg/dose.
- PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose.
- Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity.
- One of six patients receiving 2.0mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis.
- None of the six patients receiving 2.5mg/kg/dose developed DLTs, defining this as the MTD.
- The most common non-DLTs were hypertension and fatigue.
- Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13weeks.
- 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 placental growth factor (PlGF; P<0.05) from baseline was observed in response to aflibercept by day 2.