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

TitlePhase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma
Authors
Issue Date2010
Citation
Journal of Clinical Oncology, 2010, v. 28, n. 31, p. 4762-4768 How to Cite?
AbstractPurpose: 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. © 2010 by American Society of Clinical Oncology.
Persistent Identifierhttp://hdl.handle.net/10722/294436
ISSN
2020 Impact Factor: 44.544
2020 SCImago Journal Rankings: 10.482
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorBroniscer, Alberto-
dc.contributor.authorBaker, Justin N.-
dc.contributor.authorTagen, Michael-
dc.contributor.authorOnar-Thomas, Arzu-
dc.contributor.authorGilbertson, Richard J.-
dc.contributor.authorDavidoff, Andrew M.-
dc.contributor.authorPanandiker, Atmaram Pai-
dc.contributor.authorLeung, Wing-
dc.contributor.authorChin, Thomas K.-
dc.contributor.authorStewart, Clinton F.-
dc.contributor.authorKocak, Mehmet-
dc.contributor.authorRowland, Christopher-
dc.contributor.authorMerchant, Thomas E.-
dc.contributor.authorKaste, Sue C.-
dc.contributor.authorGajjar, Amar-
dc.date.accessioned2020-12-03T08:22:44Z-
dc.date.available2020-12-03T08:22:44Z-
dc.date.issued2010-
dc.identifier.citationJournal of Clinical Oncology, 2010, v. 28, n. 31, p. 4762-4768-
dc.identifier.issn0732-183X-
dc.identifier.urihttp://hdl.handle.net/10722/294436-
dc.description.abstractPurpose: 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. © 2010 by American Society of Clinical Oncology.-
dc.languageeng-
dc.relation.ispartofJournal of Clinical Oncology-
dc.titlePhase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1200/JCO.2010.30.3545-
dc.identifier.pmid20921456-
dc.identifier.pmcidPMC3020706-
dc.identifier.scopuseid_2-s2.0-78149258374-
dc.identifier.volume28-
dc.identifier.issue31-
dc.identifier.spage4762-
dc.identifier.epage4768-
dc.identifier.eissn1527-7755-
dc.identifier.isiWOS:000283585200030-
dc.identifier.issnl0732-183X-

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