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Clinical Trial
. 2016 Jul;142(7):1581-9.
doi: 10.1007/s00432-016-2161-0. Epub 2016 Apr 21.

Phase I trial of dovitinib (TKI258) in recurrent glioblastoma

Niklas Schäfer  1   2 , Gerrit H Gielen  3 , Sied Kebir  1   2 , Anja Wieland  2 , Andreas Till  2 , Frederic Mack  1 , Christina Schaub  1 , Theophilos Tzaridis  1 , Roman Reinartz  2 , Michael Niessen  1 , Rolf Fimmers  4 , Matthias Simon  5 , Christoph Coch  6 , Christine Fuhrmann  6 , Ulrich Herrlinger  1 , Björn Scheffler  2   7 , Martin Glas  8   9   10
Affiliations
Clinical Trial

Phase I trial of dovitinib (TKI258) in recurrent glioblastoma

Niklas Schäfer et al. J Cancer Res Clin Oncol. 2016 Jul.

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.

Keywords: Dovitinib; FGFR; Phase I trial; Recurrent glioblastoma; TKI258; Tyrosine kinase inhibitor.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Expression of FGFR3. Immunohistochemical FGFR3 labeling of tumor cells varied from low (a), intermediate (b), to high (c) frequencies. Scale bars, 50 µm. RT-PCR detected no FGFR3-TACC3 fusion protein in the investigated samples (d). Overexpressing plasmids were used as positive controls for PCR, and the housekeeping gene GAPDH was used to check for cDNA integrity
See this image and copyright information in PMC

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