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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)

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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.

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Conflict of interest

The authors agree that they have no conflict of interest.

Funding

CERN, Glaxo Smith Kline, Genentech.

Author information

Authors and Affiliations

  1. 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 & Maryam Fouladi

  2. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Blvd., Memphis, TN, 38105, USA

    David C. Turner & Clinton F. Stewart

  3. Division of Neuro-Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Blvd., Memphis, TN, 38105, USA

    Cynthia Wetmore, Richard Gilbertson & Amar Gajjar

  4. Department of Laboratory Medicine & Pathobiology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Cynthia Hawkins

  5. Clinical Research Division, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Carmen Jacobs

  6. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX, 77030, USA

    Ying Yuan

  7. Department of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX, 77030, USA

    Diane Liu

  8. Division of Oncology, Ann & Robert H. Lurie Children’s Hospital, 225 E Chicago Avenue, Chicago, IL, 60611, USA

    Stewart Goldman

  9. Department of Neurology, Lucille Packard Children’s Hospital at Stanford, 730 Welch Road, Ste 206, Palo Alto, CA, 94304, USA

    Paul Fisher

  10. Division of Pediatrics, The Children’s Cancer Hospital at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Michael Rytting

  11. Division of Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Eric Bouffet

  12. Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Yasmin Khakoo

  13. Department of Oncology, Children’s National Medical Center, 111 Michigan Avenue, NW, Washington, DC, 20010, USA

    Eugene I. Hwang

  14. Division of Oncology, Children’s Hospital of Colorado, 13123 East 16th Avenue, Aurora, CO, 80045, USA

    Nicholas Foreman

  15. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd., Houston, TX, 77030, USA

    Mark R. Gilbert

Authors
  1. Mariko DeWire
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  2. Maryam Fouladi
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  3. David C. Turner
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  4. Cynthia Wetmore
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  5. Cynthia Hawkins
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  6. Carmen Jacobs
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  7. Ying Yuan
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  8. Diane Liu
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  9. Stewart Goldman
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  10. Paul Fisher
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  11. Michael Rytting
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  12. Eric Bouffet
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  13. Yasmin Khakoo
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  14. Eugene I. Hwang
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  15. Nicholas Foreman
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  16. Clinton F. Stewart
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  17. Mark R. Gilbert
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  18. Richard Gilbertson
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  19. Amar Gajjar
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Corresponding author

Correspondence to Mariko DeWire.

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DeWire, M., Fouladi, M., Turner, D.C. et al. 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). J Neurooncol 123, 85–91 (2015). https://doi.org/10.1007/s11060-015-1764-7

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  • DOI: https://doi.org/10.1007/s11060-015-1764-7

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