Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma

J Clin Oncol. 2010 Nov 1;28(31):4762-8. doi: 10.1200/JCO.2010.30.3545. Epub 2010 Oct 4.

Abstract

Purpose: To evaluate the safety, maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of vandetanib, an oral vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor inhibitor, administered once daily during and after radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma.

Patients and methods: Radiotherapy was administered as 1.8-Gy fractions (total cumulative dose of 54 Gy). Vandetanib was administered concurrently with radiotherapy for a maximum of 2 years. Dose-limiting toxicities (DLTs) were evaluated during the first 6 weeks of therapy. Pharmacokinetic studies were obtained for all patients. Plasma angiogenic factors and VEGFR2 phosphorylation in mononuclear cells were analyzed before and during therapy.

Results: Twenty-one patients were administered 50 (n = 3), 65 (n = 3), 85 (n = 3), 110 (n = 6), and 145 mg/m(2) (n = 6) of vandetanib. Only one patient developed DLT (grade 3 diarrhea) at dosage level 5. An expanded cohort of patients were treated at dosage levels 4 (n = 10) and 5 (n = 4); two patients developed grade 4 hypertension and posterior reversible encephalopathy syndrome while also receiving high-dose dexamethasone. Despite significant interpatient variability, exposure to vandetanib increased with higher dosage levels. The bivariable analysis of vascular endothelial growth factor (VEGF) before and during therapy showed that patients with higher levels of VEGF before therapy had a longer progression-free survival (PFS; P = .022), whereas patients with increases in VEGF during treatment had a shorter PFS (P = .0015). VEGFR2 phosphorylation was inhibited on day 8 or 29 of therapy compared with baseline (P = .039).

Conclusion: The recommended phase II dose of vandetanib in children is 145 mg/m(2) per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Brain Stem Neoplasms / diagnosis
  • Brain Stem Neoplasms / drug therapy*
  • Brain Stem Neoplasms / radiotherapy*
  • Chemotherapy, Adjuvant
  • Child
  • Child, Preschool
  • Disease-Free Survival
  • Dose Fractionation, Radiation
  • Drug Administration Schedule
  • Female
  • Glioma / diagnosis
  • Glioma / drug therapy*
  • Glioma / radiotherapy*
  • Humans
  • Kaplan-Meier Estimate
  • Magnetic Resonance Imaging
  • Male
  • Maximum Tolerated Dose
  • Piperidines / administration & dosage*
  • Piperidines / adverse effects
  • Piperidines / pharmacokinetics*
  • Quinazolines / administration & dosage*
  • Quinazolines / adverse effects
  • Quinazolines / pharmacokinetics*
  • Radiotherapy, Adjuvant
  • Treatment Outcome
  • Young Adult

Substances

  • Antineoplastic Agents
  • Piperidines
  • Quinazolines
  • vandetanib