Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma

Journal of Neuro-oncology
David A ReardonHenry S Friedman

Abstract

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We d...Continue Reading

References

Jul 1, 1990·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·D R MacdonaldJ Gregory Cairncross
Oct 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·A J WongBert Vogelstein
Nov 26, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jeremy N RichHenry S Friedman
Mar 11, 2005·The New England Journal of Medicine·Roger StuppNational Cancer Institute of Canada Clinical Trials Group
Jul 5, 2005·Cancer Research·Michelle R StettnerCandece L Gladson
Jul 7, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Evanthia GalanisNorth Central Cancer Treatment Group
Jul 14, 2005·Investigational New Drugs·Susan ChangNorth American Brain Tumor Consortium and the National Cancer Institute
Jul 15, 2005·The New England Journal of Medicine·Frances A ShepherdNational Cancer Institute of Canada Clinical Trials Group
Mar 23, 2006·Journal of Neuro-oncology·Caren V LundBrian P Eliceiri
Aug 18, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Patrick Y WenMichael D Prados
Apr 25, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Malcolm J MooreNational Cancer Institute of Canada Clinical Trials Group
Jan 29, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michael BraveRichard Pazdur
Mar 22, 2008·Neuro-oncology·Kathleen R LambornNorth American Brain Tumor Consortium
Sep 6, 2008·Science·D Williams ParsonsKenneth W Kinzler
Feb 5, 2009·Molecular Cancer Therapeutics·Vanessa MilanoJohn de Groot
Feb 11, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Martin J van den BentThierry Gorlia
Feb 10, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Eric B HauraGerold Bepler
Feb 13, 2010·Neuro-oncology·Wenting WuMichael D Prados
Jul 10, 2010·Neuro-oncology·W K Alfred YungMichael D Prados
Oct 20, 2010·Oncogene·E F DunnD L Wheeler
Dec 15, 2010·Journal of Neuro-oncology·C Lu-EmersonP Y Wen
Mar 5, 2011·Acta Pharmacologica Sinica·Pei-pei DongLing Yang

Citations

Sep 3, 2013·Pharmaceutical Research·Linfeng WuTao L Lowe
Apr 29, 2014·Clinical Oncology : a Journal of the Royal College of Radiologists·M AjazA Chalmers
Aug 21, 2015·Expert Opinion on Investigational Drugs·Jennifer H Kang, Cory Adamson
Jun 5, 2013·Expert Opinion on Investigational Drugs·Qinglei GaoFei Ye
May 7, 2015·Pharmacology & Therapeutics·Constantinos Alifieris, Dimitrios T Trafalis
Mar 27, 2015·Neoplasia : an International Journal for Oncology Research·Hongxiang WangJuxiang Chen
Feb 12, 2015·Clinical Pharmacology and Therapeutics·K E ParrishW F Elmquist
Dec 3, 2013·Autoimmune Diseases·Norma Y Hernández-PedroJulio Sotelo
Nov 21, 2014·Journal of Neuro-oncology·Jennie W TaylorAndrew S Chi
Mar 18, 2011·Trends in Molecular Medicine·Ren-Yuan BaiGregory J Riggins
Jan 13, 2017·Topics in Magnetic Resonance Imaging : TMRI·Rebecca A Harrison, John de Groot
Jun 4, 2020·International Journal of Molecular Sciences·Filippo TorrisiSamuel Valable
Aug 16, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Channing J PallerMark J Ratain

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