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Phase I trial of dovitinib (TKI258) in recurrent glioblastoma

  • Original Article – Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Dovitinib (TKI258) is an oral multi-tyrosine kinase inhibitor of FGFR, VEGFR, PDGFR β, and c-Kit. Since dovitinib is able to cross the blood–brain barrier and targets brain tumor-relevant pathways, we conducted a phase I trial to demonstrate its safety in recurrent glioblastoma (GBM).

Patients and methods

Patients with first or second GBM recurrence started treatment with the maximal tolerated dose (MTD) previously established in systemic cancer patients (500 mg/d, 5 days on/2 days off). A modified 3 + 3 design in three cohorts (500, 400, 300 mg) was used.

Results

Twelve patients were enrolled. Seventy-two adverse events (AEs) occurred and 16.7 % of AEs were classified as ≥CTC grade 3 toxicity, mainly including hepatotoxicity and hematotoxicity. Only one out of six patients of the 300-mg cohort showed grade 3 toxicity. The PFS-6 rate was 16.7 %, and it was not associated with detection of the FGFR-TACC gene fusion in the tumor.

Conclusion

Dovitinib is safe in patients with recurrent GBM and showed efficacy in only some patients unselected for target expression. The recommended phase II dose of 300 mg would be substantially lower than the recently established MTD in systemic cancer patients. Further personalized trials are recommended.

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Acknowledgments

We thank all the patients and their relatives for participation in this trial. The trial was funded by Novartis, the manufacturer of dovitinib.

Funding

The trial was supported by Novartis Pharma GmbH Germany (internal code: CTKI258ADE02T).

Author information

Author notes

    Authors and Affiliations

    1. Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany

      Niklas Schäfer, Sied Kebir, Frederic Mack, Christina Schaub, Theophilos Tzaridis, Michael Niessen, Ulrich Herrlinger & Martin Glas

    2. Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany

      Niklas Schäfer, Sied Kebir, Anja Wieland, Andreas Till, Roman Reinartz, Björn Scheffler & Martin Glas

    3. Institute of Neuropathology, Medical Center Bonn, 53127, Bonn, Germany

      Gerrit H. Gielen

    4. Institute of Bioinformatics, Medical Center Bonn, 53127, Bonn, Germany

      Rolf Fimmers

    5. Department of Neurosurgery, Medical Center Bonn, 53127, Bonn, Germany

      Matthias Simon

    6. Study Center Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Center Bonn, 53127, Bonn, Germany

      Christoph Coch & Christine Fuhrmann

    7. Division of Translational Oncology/Neurooncology, German Cancer Research Center (DKFZ), Heidelberg; West German Cancer Center (WTZ) and German Cancer Consortium (DKTK), University Hospital Essen, 45147, Essen, Germany

      Björn Scheffler

    8. Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Klinik, 53129, Bonn, Germany

      Martin Glas

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    1. Niklas Schäfer
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    2. Gerrit H. Gielen
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    Corresponding author

    Correspondence to Martin Glas.

    Ethics declarations

    Conflict of interest

    Niklas Schäfer and Frederic Mack received honoraria and travel fees from Roche. Ulrich Herrlinger received honoraria from Roche and Mundipharma, has a consulting role to declare for Roche and Mundipharma, and received research funding from Roche and Medac. Martin Glas received honoraria from Roche and Mundipharma, has a consulting role to declare for Novartis, Roche, Mundipharma, received travel fees from Medac, and received research funding from Novartis. All other authors declare that they have no conflict of interest.

    Ethical standards

    The trial was registered (EudraCT No. 2012-005460-95; ClinicalTrials.gov: NCT01972750) and approved by the local ethical committee. All patients gave written consent before performing of any study-related activity. All trial procedures adhered to the principles of the Declaration of Helsinki and the Guidelines of Good Clinical Practice.

    Additional information

    Björn Scheffler and Martin Glas have contributed equally.

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    Schäfer, N., Gielen, G.H., Kebir, S. et al. Phase I trial of dovitinib (TKI258) in recurrent glioblastoma. J Cancer Res Clin Oncol 142, 1581–1589 (2016). https://doi.org/10.1007/s00432-016-2161-0

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