Phase I trial of dovitinib (TKI258) in recurrent glioblastoma.
OBJECTIVE
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).


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.


CONCLUSIONS
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.
Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany.|Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany.
Niklas
N
Schäfer
Institute of Neuropathology, Medical Center Bonn, 53127, Bonn, Germany.
Gerrit H
GH
Gielen
Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany.|Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany.
Sied
S
Kebir
Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany.
Anja
A
Wieland
Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany.
Andreas
A
Till
Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany.
Frederic
F
Mack
Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany.
Christina
C
Schaub
Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany.
Theophilos
T
Tzaridis
Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany.
Roman
R
Reinartz
Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany.
Michael
M
Niessen
Institute of Bioinformatics, Medical Center Bonn, 53127, Bonn, Germany.
Rolf
R
Fimmers
Department of Neurosurgery, Medical Center Bonn, 53127, Bonn, Germany.
Matthias
M
Simon
Study Center Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Center Bonn, 53127, Bonn, Germany.
Christoph
C
Coch
Study Center Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Center Bonn, 53127, Bonn, Germany.
Christine
C
Fuhrmann
Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany.
Ulrich
U
Herrlinger
Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany.|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
B
Scheffler
Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany. Martin.Glas@ukb.uni-bonn.de.|Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany. Martin.Glas@ukb.uni-bonn.de.|Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Klinik, 53129, Bonn, Germany. Martin.Glas@ukb.uni-bonn.de.
Martin
M
Glas
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy*; D015331:Cohort Studies; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism
C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D008869:Microtubule-Associated Proteins; D015363:Quinolones; C120551:TACC3 protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
Dovitinib; FGFR; Phase I trial; Recurrent glioblastoma; TKI258; Tyrosine kinase inhibitor