PMID- 27100354 OWN - NLM STAT- MEDLINE DCOM- 20170217 LR - 20181113 IS - 1432-1335 (Electronic) IS - 0171-5216 (Linking) VI - 142 IP - 7 DP - 2016 Jul TI - Phase I trial of dovitinib (TKI258) in recurrent glioblastoma. PG - 1581-9 LID - 10.1007/s00432-016-2161-0 [doi] AB - PURPOSE: Dovitinib (TKI258) is an oral multi-tyrosine kinase inhibitor of FGFR, VEGFR, PDGFR beta, 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. FAU - Schafer, Niklas AU - Schafer N AD - Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany. AD - Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany. FAU - Gielen, Gerrit H AU - Gielen GH AD - Institute of Neuropathology, Medical Center Bonn, 53127, Bonn, Germany. FAU - Kebir, Sied AU - Kebir S AD - Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany. AD - Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany. FAU - Wieland, Anja AU - Wieland A AD - Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany. FAU - Till, Andreas AU - Till A AD - Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany. FAU - Mack, Frederic AU - Mack F AD - Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany. FAU - Schaub, Christina AU - Schaub C AD - Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany. FAU - Tzaridis, Theophilos AU - Tzaridis T AD - Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany. FAU - Reinartz, Roman AU - Reinartz R AD - Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany. FAU - Niessen, Michael AU - Niessen M AD - Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany. FAU - Fimmers, Rolf AU - Fimmers R AD - Institute of Bioinformatics, Medical Center Bonn, 53127, Bonn, Germany. FAU - Simon, Matthias AU - Simon M AD - Department of Neurosurgery, Medical Center Bonn, 53127, Bonn, Germany. FAU - Coch, Christoph AU - Coch C AD - Study Center Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Center Bonn, 53127, Bonn, Germany. FAU - Fuhrmann, Christine AU - Fuhrmann C AD - Study Center Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, Medical Center Bonn, 53127, Bonn, Germany. FAU - Herrlinger, Ulrich AU - Herrlinger U AD - Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany. FAU - Scheffler, Bjorn AU - Scheffler B AD - Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany. AD - 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. FAU - Glas, Martin AU - Glas M AD - Division of Clinical Neurooncology, Department of Neurology, Medical Center Bonn, 53127, Bonn, Germany. Martin.Glas@ukb.uni-bonn.de. AD - Stem Cell Pathologies, Institute of Reconstructive Neurobiology, University of Bonn, 53127, Bonn, Germany. Martin.Glas@ukb.uni-bonn.de. AD - Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Klinik, 53129, Bonn, Germany. Martin.Glas@ukb.uni-bonn.de. LA - eng PT - Clinical Trial, Phase I PT - Journal Article DEP - 20160421 PL - Germany TA - J Cancer Res Clin Oncol JT - Journal of cancer research and clinical oncology JID - 7902060 RN - 0 (4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one) RN - 0 (Antineoplastic Agents) RN - 0 (Benzimidazoles) RN - 0 (Biomarkers, Tumor) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Quinolones) RN - 0 (TACC3 protein, human) RN - EC 2.7.10.1 (FGFR3 protein, human) RN - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 3) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/administration & dosage/adverse effects/*therapeutic use MH - Benzimidazoles/administration & dosage/adverse effects/*therapeutic use MH - Biomarkers, Tumor/metabolism MH - Brain Neoplasms/*drug therapy MH - Cohort Studies MH - Female MH - Glioblastoma/*drug therapy MH - Humans MH - Male MH - Microtubule-Associated Proteins/metabolism MH - Middle Aged MH - Quinolones/administration & dosage/adverse effects/*therapeutic use MH - Receptor, Fibroblast Growth Factor, Type 3/metabolism OTO - NOTNLM OT - Dovitinib OT - FGFR OT - Phase I trial OT - Recurrent glioblastoma OT - TKI258 OT - Tyrosine kinase inhibitor EDAT- 2016/04/22 06:00 MHDA- 2017/02/18 06:00 CRDT- 2016/04/22 06:00 PHST- 2016/03/02 00:00 [received] PHST- 2016/04/07 00:00 [accepted] PHST- 2016/04/22 06:00 [entrez] PHST- 2016/04/22 06:00 [pubmed] PHST- 2017/02/18 06:00 [medline] AID - 10.1007/s00432-016-2161-0 [pii] AID - 10.1007/s00432-016-2161-0 [doi] PST - ppublish SO - J Cancer Res Clin Oncol. 2016 Jul;142(7):1581-9. doi: 10.1007/s00432-016-2161-0. Epub 2016 Apr 21.