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/m(2)/dose to the first 10 patients, and then 700 mg/m(2)/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.
authors: Division of Oncology, Hematology/Oncology Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC 7015, 3333 Burnet Avenue, Cincinnati, OH, 45225, USA, mariko.dewire@cchmc.org.
authors: Mariko
authors: M
authors: DeWire
authors: Maryam
authors: M
authors: Fouladi
authors: David C
authors: DC
authors: Turner
authors: Cynthia
authors: C
authors: Wetmore
authors: Cynthia
authors: C
authors: Hawkins
authors: Carmen
authors: C
authors: Jacobs
authors: Ying
authors: Y
authors: Yuan
authors: Diane
authors: D
authors: Liu
authors: Stewart
authors: S
authors: Goldman
authors: Paul
authors: P
authors: Fisher
authors: Michael
authors: M
authors: Rytting
authors: Eric
authors: E
authors: Bouffet
authors: Yasmin
authors: Y
authors: Khakoo
authors: Eugene I
authors: EI
authors: Hwang
authors: Nicholas
authors: N
authors: Foreman
authors: Clinton F
authors: CF
authors: Stewart
authors: Mark R
authors: MR
authors: Gilbert
authors: Richard
authors: R
authors: Gilbertson
authors: Amar
authors: A
authors: Gajjar
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004806:Ependymoma / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077341:Lapatinib; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage; D016879:Salvage Therapy; D015996:Survival Rate; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D011799:Quinazolines; D000077341:Lapatinib; D000068258:Bevacizumab