An open-label, two-stage, phase II study of bevacizumab and lapatinib in children with recurrent or refractory ependymoma: A Collaborative Ependymoma Research Network study (CERN) Journal Article
| Authors: | DeWire, M.; Fouladi, M.; Turner, D. C.; Wetmore, C.; Hawkins, C.; Jacobs, C.; Yuan, Y.; Liu, D.; Goldman, S.; Fisher, P.; Rytting, M.; Bouffet, E.; Khakoo, Y.; Hwang, E. I.; Foreman, N.; Stewart, C. F.; Gilbert, M. R.; Gilbertson, R.; Gajjar, A. |
| Article Title: | An open-label, two-stage, phase II study of bevacizumab and lapatinib in children with recurrent or refractory ependymoma: A Collaborative Ependymoma Research Network study (CERN) |
| Abstract: | Co-expression of ERBB2 and ERBB4, reported in 75 % of pediatric ependymomas, correlates with worse overall survival. Lapatinib, a selective ERBB1 and ERBB2 inhibitor has produced prolonged disease stabilization in patients with ependymoma in a phase I study. Bevacizumab exposure in ependymoma xenografts leads to ablation of tumor self-renewing cells, arresting growth. Thus, we conducted an open-label, phase II study of bevacizumab and lapatinib in children with recurrent ependymomas. Patients ≤21 years of age with recurrent ependymoma received lapatinib orally twice daily (900 mg/m2/dose to the first 10 patients, and then 700 mg/m2/dose) and bevacizumab 10 mg/kg intravenously on days 1 and 15 of a 28-day course. Lapatinib serum trough levels were analyzed prior to each course. Total and phosphorylated VEGFR2 expression was measured in peripheral blood mononuclear cells (PBMCs) before doses 1 and 2 of bevacizumab and 24–48 h following dose 2 of bevacizumab. Twenty-four patients with a median age of 10 years (range 2–21 years) were enrolled; 22 were eligible and 20 evaluable for response. Thirteen had anaplastic ependymoma. There were no objective responses; 4 patients had stable disease for ≥4 courses (range 4–14). Grade 3 toxicities included rash, elevated ALT, and diarrhea. Grade 4 toxicities included peri-tracheostomy hemorrhage (n = 1) and elevated creatinine phosphokinase (n = 1). The median lapatinib pre-dose trough concentration was 3.72 µM. Although the combination of bevacizumab and lapatinib was well tolerated in children with recurrent ependymoma, it proved ineffective. © 2015, Springer Science+Business Media New York. |
| Keywords: | adolescent; adult; child; clinical article; controlled study; protein phosphorylation; treatment response; overall survival; drug tolerability; fatigue; neutropenia; bevacizumab; diarrhea; drug dose reduction; drug efficacy; hypertension; anorexia; progression free survival; infection; liver toxicity; multiple cycle treatment; phase 2 clinical trial; bleeding; nausea; thrombocytopenia; vomiting; vasculotropin receptor 2; abdominal pain; alanine aminotransferase blood level; aspartate aminotransferase blood level; fever; lymphocytopenia; rash; alanine aminotransferase; aspartate aminotransferase; heart infarction; vein thrombosis; transient ischemic attack; recurrent disease; ependymoma; open study; creatine kinase; drug blood level; phase 1 clinical trial; drug half life; children; digestive system perforation; wound dehiscence; brain hemorrhage; lapatinib; artery thrombosis; heart muscle ischemia; peripheral blood mononuclear cell; drug exposure; cerebrovascular accident; upper respiratory tract infection; desquamation; creatine kinase blood level; recurrent ependymoma; posterior reversible encephalopathy syndrome; eosinophilia; digestive system fistula; digestive system disease; abdominal tenderness; left ventricular systolic dysfunction; human; male; female; article; gastrointestinal leak |
| Journal Title: | Journal of Neuro-Oncology |
| Volume: | 123 |
| Issue: | 1 |
| ISSN: | 0167-594X |
| Publisher: | Springer |
| Date Published: | 2015-05-01 |
| Start Page: | 85 |
| End Page: | 91 |
| Language: | English |
| DOI: | 10.1007/s11060-015-1764-7 |
| PROVIDER: | scopus |
| PUBMED: | 25859842 |
| PMCID: | PMC4992988 |
| DOI/URL: | |
| Notes: | Export Date: 2 July 2015 -- Source: Scopus |
