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

Julia Glade Bender, Susan M. Blaney, Scott Borinstein, Joel M. Reid, Sylvain Baruchel, Charlotte Ahern, Ashish M. Ingle, Darrell J. Yamashiro, Alice Chen, Brenda Weigel, Peter C. Adamson, Julie R. Park

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5081-5089
Number of pages9
JournalClinical Cancer Research
Volume18
Issue number18
DOIs
StatePublished - Sep 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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