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

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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

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Pharmacokinetics
Maximum Tolerated Dose
Neoplasms
Vascular Endothelial Growth Factor A
Clear Cell Sarcoma
Hemorrhage
Hepatoblastoma
Nociceptive Pain
aflibercept
Fatigue
Hepatocellular Carcinoma
Intercellular Signaling Peptides and Proteins
Research Design
Necrosis
Biomarkers
Pediatrics
Hypertension
Pain
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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

In: Clinical Cancer Research, Vol. 18, No. 18, 15.09.2012, p. 5081-5089.

Research output: Contribution to journalArticle

Bender, JG, Blaney, SM, Borinstein, S, Reid, JM, Baruchel, S, Ahern, C, Ingle, AM, Yamashiro, DJ, Chen, A, Weigel, B, Adamson, PC & Park, JR 2012, '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, vol. 18, no. 18, pp. 5081-5089. https://doi.org/10.1158/1078-0432.CCR-12-0078
Bender, Julia Glade ; Blaney, Susan M. ; Borinstein, Scott ; Reid, Joel M ; Baruchel, Sylvain ; Ahern, Charlotte ; Ingle, Ashish M. ; Yamashiro, Darrell J. ; Chen, Alice ; Weigel, Brenda ; Adamson, Peter C. ; Park, Julie R. / 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. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 18. pp. 5081-5089.
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T1 - A phase I trial and pharmacokinetic study of aflibercept (VEGF trap) in children with refractory solid tumors

T2 - A Children's Oncology Group phase I consortium report

AU - Bender, Julia Glade

AU - Blaney, Susan M.

AU - Borinstein, Scott

AU - Reid, Joel M

AU - Baruchel, Sylvain

AU - Ahern, Charlotte

AU - Ingle, Ashish M.

AU - Yamashiro, Darrell J.

AU - Chen, Alice

AU - Weigel, Brenda

AU - Adamson, Peter C.

AU - Park, Julie R.

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N2 - 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.

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