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

Clin Cancer Res. 2012 Sep 15;18(18):5081-9. doi: 10.1158/1078-0432.CCR-12-0078. Epub 2012 Jul 12.

Abstract

Purpose: Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept.

Experimental design: Cohorts of three to six 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 conducted with the initial dose.

Results: Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/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 >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 placental growth factor (PlGF; P < 0.05) from baseline was observed in response to aflibercept by day 2.

Conclusions: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than 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 antitumor activity but were dose-limiting.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers / blood
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Humans
  • Infant
  • Male
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Receptors, Vascular Endothelial Growth Factor / adverse effects
  • Receptors, Vascular Endothelial Growth Factor / pharmacokinetics
  • Receptors, Vascular Endothelial Growth Factor / therapeutic use*
  • Recombinant Fusion Proteins / adverse effects
  • Recombinant Fusion Proteins / pharmacokinetics
  • Recombinant Fusion Proteins / therapeutic use*
  • Treatment Outcome
  • Young Adult

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Recombinant Fusion Proteins
  • aflibercept
  • Receptors, Vascular Endothelial Growth Factor