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Journal of Neuro-Oncology

, Volume 121, Issue 2, pp 297–302 | Cite as

Phase II trial of triple tyrosine kinase receptor inhibitor nintedanib in recurrent high-grade gliomas

  • Andrew D. NordenEmail author
  • David Schiff
  • Manmeet S. Ahluwalia
  • Glenn J. Lesser
  • Lakshmi Nayak
  • Eudocia Q. Lee
  • Mikael L. Rinne
  • Alona Muzikansky
  • Jorg Dietrich
  • Benjamin Purow
  • Lisa M. Doherty
  • Debra C. LaFrankie
  • Julee R. Pulverenti
  • Jennifer A. Rifenburg
  • Sandra F. Ruland
  • Katrina H. Smith
  • Sarah C. Gaffey
  • Christine McCluskey
  • Keith L. Ligon
  • David A. Reardon
  • Patrick Y. Wen
Clinical Study

Abstract

Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF signaling and increased PDGF-mediated pericyte coverage. Nintedanib is an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/β, FGFR 1-3, and VEGFR 1-3 that may overcome resistance to anti-VEGF therapy. This was a two-stage phase II trial in adults with first or second recurrence of GBM, stratified by prior bevacizumab therapy (ClinicalTrials.gov number NCT01380782; 1199.94). The primary endpoint was PFS6 in the bevacizumab-naive arm (Arm A) and PFS3 in the post-bevacizumab arm (Arm B). Up to 10 anaplastic glioma (AG) patients were accrued to each arm in exploratory cohorts. Twenty-two patients enrolled in Arm A and 14 in Arm B. Arm A included 12 GBMs (55 %), 13 patients with one prior regimen (59 %), and median age 54 years (range 28–75). Arm B included 10 GBMs (71 %), one patient with one prior regimen (7 %), and median age 52 years (range 32–70). Median KPS overall was 90 (range 60–100). There were no responses. In Arm A (GBM only), PFS6 was 0 %, median PFS 28 days (95 % CI 27–83), and median OS 6.9 months (3.7–8.1). In Arm B (GBM only), PFS3 was 0 %, median PFS 28 days (22–28), and median OS 2.6 months (1.0–6.9). Among AG patients in each arm, PFS6 was 0 %. Treatment was well tolerated. In conclusion, nintedanib is not active against recurrent high-grade glioma, regardless of prior bevacizumab therapy.

Keywords

High-grade glioma Nintedanib Anti-angiogenic therapy 

Notes

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Andrew D. Norden
    • 1
    • 2
    • 3
    Email author
  • David Schiff
    • 4
  • Manmeet S. Ahluwalia
    • 5
  • Glenn J. Lesser
    • 6
  • Lakshmi Nayak
    • 1
    • 2
    • 3
  • Eudocia Q. Lee
    • 1
    • 2
    • 3
  • Mikael L. Rinne
    • 1
    • 2
    • 3
  • Alona Muzikansky
    • 7
  • Jorg Dietrich
    • 8
  • Benjamin Purow
    • 4
  • Lisa M. Doherty
    • 2
  • Debra C. LaFrankie
    • 2
  • Julee R. Pulverenti
    • 2
  • Jennifer A. Rifenburg
    • 2
  • Sandra F. Ruland
    • 2
  • Katrina H. Smith
    • 2
  • Sarah C. Gaffey
    • 2
  • Christine McCluskey
    • 2
  • Keith L. Ligon
    • 3
    • 9
    • 10
  • David A. Reardon
    • 2
    • 3
  • Patrick Y. Wen
    • 1
    • 2
    • 3
  1. 1.Division of Neuro-Oncology, Department of NeurologyBrigham and Women’s HospitalBostonUSA
  2. 2.Center for Neuro-OncologyDana-Farber Cancer InstituteBostonUSA
  3. 3.Harvard Medical SchoolBostonUSA
  4. 4.University of Virginia School of MedicineCharlottesvilleUSA
  5. 5.Cleveland ClinicClevelandUSA
  6. 6.Comprehensive Cancer Center of Wake Forest University, Medical Center BoulevardWinston-SalemUSA
  7. 7.Massachusetts General Hospital Biostatistics CenterBostonUSA
  8. 8.Pappas Center for Neuro-OncologyMassachusetts General Hospital Cancer CenterBostonUSA
  9. 9.Department of Medical Oncology, Center for Molecular Oncologic PathologyDana-Farber Cancer InstituteBostonUSA
  10. 10.Department of PathologyBrigham and Women’s HospitalBostonUSA

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