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Journal of Neuro-Oncology

, Volume 123, Issue 1, pp 85–91 | Cite as

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)

  • Mariko DeWireEmail author
  • Maryam Fouladi
  • David C. Turner
  • Cynthia Wetmore
  • Cynthia Hawkins
  • Carmen Jacobs
  • Ying Yuan
  • Diane Liu
  • Stewart Goldman
  • Paul Fisher
  • Michael Rytting
  • Eric Bouffet
  • Yasmin Khakoo
  • Eugene I. Hwang
  • Nicholas Foreman
  • Clinton F. Stewart
  • Mark R. Gilbert
  • Richard Gilbertson
  • Amar Gajjar
Clinical Study

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.

Keywords

Children Recurrent ependymoma Lapatinib Bevacizumab 

Notes

Conflict of interest

The authors agree that they have no conflict of interest.

Funding

CERN, Glaxo Smith Kline, Genentech.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Mariko DeWire
    • 1
    Email author
  • Maryam Fouladi
    • 1
  • David C. Turner
    • 2
  • Cynthia Wetmore
    • 3
  • Cynthia Hawkins
    • 4
  • Carmen Jacobs
    • 5
  • Ying Yuan
    • 6
  • Diane Liu
    • 7
  • Stewart Goldman
    • 8
  • Paul Fisher
    • 9
  • Michael Rytting
    • 10
  • Eric Bouffet
    • 11
  • Yasmin Khakoo
    • 12
  • Eugene I. Hwang
    • 13
  • Nicholas Foreman
    • 14
  • Clinton F. Stewart
    • 2
  • Mark R. Gilbert
    • 15
  • Richard Gilbertson
    • 3
  • Amar Gajjar
    • 3
  1. 1.Division of Oncology, Hematology/Oncology Cancer and Blood Diseases InstituteCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  2. 2.Department of Pharmaceutical SciencesSt. Jude Children’s Research HospitalMemphisUSA
  3. 3.Division of Neuro-OncologySt. Jude Children’s Research HospitalMemphisUSA
  4. 4.Department of Laboratory Medicine & PathobiologyThe Hospital for Sick ChildrenTorontoCanada
  5. 5.Clinical Research DivisionThe University of Texas MD Anderson Cancer CenterHoustonUSA
  6. 6.Department of BiostatisticsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  7. 7.Department of Quantitative SciencesThe University of Texas MD Anderson Cancer CenterHoustonUSA
  8. 8.Division of OncologyAnn & Robert H. Lurie Children’s HospitalChicagoUSA
  9. 9.Department of NeurologyLucille Packard Children’s Hospital at StanfordPalo AltoUSA
  10. 10.Division of PediatricsThe Children’s Cancer Hospital at The University of Texas MD Anderson Cancer CenterHoustonUSA
  11. 11.Division of OncologyThe Hospital for Sick ChildrenTorontoCanada
  12. 12.Department of NeurologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  13. 13.Department of OncologyChildren’s National Medical CenterWashingtonUSA
  14. 14.Division of OncologyChildren’s Hospital of ColoradoAuroraUSA
  15. 15.Department of Neuro-OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

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