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

Alberto Broniscer, Justin N. Baker, Michael Tagen, Arzu Onar-Thomas, Richard J. Gilbertson, Andrew M. Davidoff, Atmaram Pai Panandiker, Wing Leung, Thomas K. Chin, Clinton F. Stewart, Mehmet Kocak, Christopher Rowland, Thomas E. Merchant, Sue C. Kaste, Amar Gajjar

Research output: Contribution to journalArticle

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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/m2 (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/m2 per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids.

Original languageEnglish (US)
Pages (from-to)4762-4768
Number of pages7
JournalJournal of Clinical Oncology
Volume28
Issue number31
DOIs
StatePublished - Nov 1 2010

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Glioma
Radiotherapy
Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor A
Therapeutics
Pharmacokinetics
Phosphorylation
Posterior Leukoencephalopathy Syndrome
Hypertension
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
Maximum Tolerated Dose
Angiogenesis Inducing Agents
Epidermal Growth Factor Receptor
Dexamethasone
Disease-Free Survival
Diarrhea
Adrenal Cortex Hormones
Safety

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Broniscer, A., Baker, J. N., Tagen, M., Onar-Thomas, A., Gilbertson, R. J., Davidoff, A. M., ... Gajjar, A. (2010). Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. Journal of Clinical Oncology, 28(31), 4762-4768. https://doi.org/10.1200/JCO.2010.30.3545

Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. / Broniscer, Alberto; Baker, Justin N.; Tagen, Michael; Onar-Thomas, Arzu; Gilbertson, Richard J.; Davidoff, Andrew M.; Panandiker, Atmaram Pai; Leung, Wing; Chin, Thomas K.; Stewart, Clinton F.; Kocak, Mehmet; Rowland, Christopher; Merchant, Thomas E.; Kaste, Sue C.; Gajjar, Amar.

In: Journal of Clinical Oncology, Vol. 28, No. 31, 01.11.2010, p. 4762-4768.

Research output: Contribution to journalArticle

Broniscer, A, Baker, JN, Tagen, M, Onar-Thomas, A, Gilbertson, RJ, Davidoff, AM, Panandiker, AP, Leung, W, Chin, TK, Stewart, CF, Kocak, M, Rowland, C, Merchant, TE, Kaste, SC & Gajjar, A 2010, 'Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma', Journal of Clinical Oncology, vol. 28, no. 31, pp. 4762-4768. https://doi.org/10.1200/JCO.2010.30.3545
Broniscer, Alberto ; Baker, Justin N. ; Tagen, Michael ; Onar-Thomas, Arzu ; Gilbertson, Richard J. ; Davidoff, Andrew M. ; Panandiker, Atmaram Pai ; Leung, Wing ; Chin, Thomas K. ; Stewart, Clinton F. ; Kocak, Mehmet ; Rowland, Christopher ; Merchant, Thomas E. ; Kaste, Sue C. ; Gajjar, Amar. / Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 31. pp. 4762-4768.
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T1 - Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma

AU - Broniscer, Alberto

AU - Baker, Justin N.

AU - Tagen, Michael

AU - Onar-Thomas, Arzu

AU - Gilbertson, Richard J.

AU - Davidoff, Andrew M.

AU - Panandiker, Atmaram Pai

AU - Leung, Wing

AU - Chin, Thomas K.

AU - Stewart, Clinton F.

AU - Kocak, Mehmet

AU - Rowland, Christopher

AU - Merchant, Thomas E.

AU - Kaste, Sue C.

AU - Gajjar, Amar

PY - 2010/11/1

Y1 - 2010/11/1

N2 - 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/m2 (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/m2 per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids.

AB - 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/m2 (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/m2 per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids.

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