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Tytuł pozycji:

Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy-the MecMeth/NOA-24 trial.

Tytuł:
Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy-the MecMeth/NOA-24 trial.
Autorzy:
Zeyen T; Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany.
Potthoff AL; Department of Neurosurgery and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany.
Nemeth R; Institute of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany.
Heiland DH; Department of Neurosurgery, University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Burger MC; Dr. Senckenberg Institute of Neurooncology, Goethe-University Hospital, Frankfurt am Main, Germany.
Steinbach JP; Dr. Senckenberg Institute of Neurooncology, Goethe-University Hospital, Frankfurt am Main, Germany.
Hau P; Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany.
Tabatabai G; Interdisciplinary Division of Neurooncology, University of Tübingen, Tübingen, Germany.
Glas M; Division of Clinical Neurooncology, Department of Neurology, University Hospital Essen, Essen, Germany.
Schlegel U; Department of Neurology, University Hospital Knappschaftskrankenhaus, Ruhr-Universität Bochum, Bochum, Germany.
Grauer O; Department of Neurology, University of Münster, Münster, Germany.
Krex D; Department of Neurosurgery, University of Dresden, Dresden, Germany.
Schnell O; Department of Neurosurgery, University of Freiburg, Freiburg, Germany.; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Goldbrunner R; Department of Neurosurgery, University of Cologne, Cologne, Germany.
Sabel M; Department of Neurosurgery, University of Düsseldorf, Düsseldorf, Germany.
Thon N; Department of Neurosurgery, Ludwig Maximillian University of Munich and German Cancer Consortium, Partner Site Munich, Munich, Germany.
Delev D; Department of Neurosurgery, University Hospital RWTH Aachen, Aachen, Germany.
Clusmann H; Department of Neurosurgery, University Hospital RWTH Aachen, Aachen, Germany.
Seidel C; Department of Radiotherapy and Radiation Oncology, University of Leipzig, Leipzig, Germany.
Güresir E; Department of Neurosurgery and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany.
Schmid M; Institute of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany.
Schuss P; Department of Neurosurgery and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany.
Giordano FA; Department of Radiation Oncology, University Hospital Bonn, Bonn, Germany.
Radbruch A; Department of Neuroradiology, University Hospital Bonn, Bonn, Germany.
Becker A; Department of Neuropathology, University Hospital Bonn, Bonn, Germany.
Weller J; Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany.
Schaub C; Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany.
Vatter H; Department of Neurosurgery and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany.
Schilling J; Clinical Study Core Unit Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, University Bonn, Bonn, Germany.
Winkler F; Department of Neurology, University Hospital Heidelberg, Neurooncology Program at the National Center for Tumor Disease, German Cancer Consortium (DKTK), Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Herrlinger U; Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany.
Schneider M; Department of Neurosurgery and Center of Integrated Oncology, University Hospital Bonn, Bonn, Germany. .
Źródło:
Trials [Trials] 2022 Jan 19; Vol. 23 (1), pp. 57. Date of Electronic Publication: 2022 Jan 19.
Typ publikacji:
Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Randomized Controlled Trial
Język:
English
Imprint Name(s):
Original Publication: [London] : BioMed Central, 2006-
MeSH Terms:
Glioblastoma*/drug therapy
Glioblastoma*/genetics
Antineoplastic Agents, Alkylating/adverse effects ; DNA Modification Methylases/therapeutic use ; DNA Repair Enzymes/genetics ; DNA Repair Enzymes/therapeutic use ; Humans ; Meclofenamic Acid/therapeutic use ; Neoplasm Recurrence, Local ; Temozolomide/adverse effects ; Tumor Suppressor Proteins/therapeutic use
References:
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Gately L, McLachlan SA, Dowling A, Philip J. Life beyond a diagnosis of glioblastoma: a systematic review of the literature. J Cancer Survivorship Res Practice. 2017;11(4):447–52. (PMID: 10.1007/s11764-017-0602-7)
Herrlinger U, Tzaridis T, Mack F, Steinbach JP, Schlegel U, Sabel M, et al. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial. Lancet. 2019;393(10172):678–88. https://doi.org/10.1016/S0140-6736(18)31791-4 . (PMID: 10.1016/S0140-6736(18)31791-430782343)
Perry JR, Belanger K, Mason WP, Fulton D, Kavan P, Easaw J, et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010;28(12):2051–7. (PMID: 10.1200/JCO.2009.26.5520)
Weller M, Tabatabai G, Kastner B, Felsberg J, Steinbach JP, Wick A, et al. MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR trial. Clin Cancer Res. 2015;21(9):2057–64. https://doi.org/10.1158/1078-0432.CCR-14-2737 . (PMID: 10.1158/1078-0432.CCR-14-273725655102)
Osswald M, Jung E, Sahm F, Solecki G, Venkataramani V, Blaes J, et al. Brain tumour cells interconnect to a functional and resistant network. Nature. 2015;528(7580):93–8. https://doi.org/10.1038/nature16071 . (PMID: 10.1038/nature1607126536111)
Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature. 2019;573(7775):532–8. https://doi.org/10.1038/s41586-019-1564-x . (PMID: 10.1038/s41586-019-1564-x31534219)
Venkatesh HS, Morishita W, Geraghty AC, Silverbush D, Gillespie SM, Arzt M, et al. Electrical and synaptic integration of glioma into neural circuits. Nature. 2019;573(7775):539–45. https://doi.org/10.1038/s41586-019-1563-y . (PMID: 10.1038/s41586-019-1563-y315342227038898)
Weil S, Osswald M, Solecki G, Grosch J, Jung E, Lemke D, et al. Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas. Neuro Oncol. 2017;19(10):1316–26. https://doi.org/10.1093/neuonc/nox070 . (PMID: 10.1093/neuonc/nox070284193035596180)
Munoz JL, Rodriguez-Cruz V, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P. Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43. Cell Death Dis. 2014;5(3):e1145. https://doi.org/10.1038/cddis.2014.111 . (PMID: 10.1038/cddis.2014.111246754633973225)
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Schneider M, Potthoff AL, Evert BO, Dicks M, Ehrentraut D, Dolf A, et al. Inhibition of intercellular cytosolic traffic via gap junctions reinforces lomustine-induced toxicity in glioblastoma independent of MGMT promoter methylation status. Pharmaceuticals. 2021;14(3).
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Grant Information:
01EN2008 bundesministerium für bildung und forschung
Contributed Indexing:
Keywords: Glioblastoma; Meclofenamate; Relapse; Second-line therapy; Temozolomide
Substance Nomenclature:
0 (Antineoplastic Agents, Alkylating)
0 (Tumor Suppressor Proteins)
48I5LU4ZWD (Meclofenamic Acid)
EC 2.1.1.- (DNA Modification Methylases)
EC 2.1.1.63 (MGMT protein, human)
EC 6.5.1.- (DNA Repair Enzymes)
YF1K15M17Y (Temozolomide)
Entry Date(s):
Date Created: 20220120 Date Completed: 20220121 Latest Revision: 20220517
Update Code:
20240105
PubMed Central ID:
PMC8767701
DOI:
10.1186/s13063-021-05977-0
PMID:
35045869
Czasopismo naukowe
Background: Glioblastoma is the most frequent and malignant primary brain tumor. Even in the subgroup with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and favorable response to first-line therapy, survival after relapse is short (12 months). Standard therapy for recurrent MGMT-methylated glioblastoma is not standardized and may consist of re-resection, re-irradiation, and chemotherapy with temozolomide (TMZ), lomustine (CCNU), or a combination thereof. Preclinical results show that meclofenamate (MFA), originally developed as a nonsteroidal anti-inflammatory drug (NSAID) and registered in the USA, sensitizes glioblastoma cells to temozolomide-induced toxicity via inhibition of gap junction-mediated intercellular cytosolic traffic and demolishment of tumor microtube (TM)-based network morphology.
Methods: In this study, combined MFA/TMZ therapy will be administered (orally) in patients with first relapse of MGMT-methylated glioblastoma. A phase I component (6-12 patients, 2 dose levels of MFA + standard dose TMZ) evaluates safety and feasibility and determines the dose for the randomized phase II component (2 × 30 patients) with progression-free survival as the primary endpoint.
Discussion: This study is set up to assess toxicity and first indications of efficacy of MFA repurposed in the setting of a very difficult-to-treat recurrent tumor. The trial is a logical next step after the identification of the role of resistance-providing TMs in glioblastoma, and results will be crucial for further trials targeting TMs. In case of favorable results, MFA may constitute the first clinically feasible TM-targeted drug and therefore might bridge the idea of a TM-targeted therapeutic approach from basic insights into clinical reality.
Trial Registration: EudraCT 2021-000708-39 . Registered on 08 February 2021.
(© 2022. The Author(s).)
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