Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial
Thomas Zeyen,
Anna-Laura Potthoff,
Robert Nemeth,
Dieter H. Heiland,
Michael C. Burger,
Joachim P. Steinbach,
Peter Hau,
Ghazaleh Tabatabai,
Martin Glas,
Uwe Schlegel,
Oliver Grauer,
Dietmar Krex,
Oliver Schnell,
Roland Goldbrunner,
Michael Sabel,
Niklas Thon,
Daniel Delev,
Hans Clusmann,
Clemens Seidel,
Erdem Güresir,
Matthias Schmid,
Patrick Schuss,
Frank A. Giordano,
Alexander Radbruch,
Albert Becker,
Johannes Weller,
Christina Schaub,
Hartmut Vatter,
Judith Schilling,
Frank Winkler,
Ulrich Herrlinger,
Matthias Schneider
Affiliations
Thomas Zeyen
Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn
Anna-Laura Potthoff
Department of Neurosurgery and Center of Integrated Oncology, University Hospital Bonn
Robert Nemeth
Institute of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn
Dieter H. Heiland
Department of Neurosurgery, University of Freiburg
Michael C. Burger
Dr. Senckenberg Institute of Neurooncology, Goethe-University Hospital
Joachim P. Steinbach
Dr. Senckenberg Institute of Neurooncology, Goethe-University Hospital
Peter Hau
Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg
Ghazaleh Tabatabai
Interdisciplinary Division of Neurooncology, University of Tübingen
Martin Glas
Division of Clinical Neurooncology, Department of Neurology, University Hospital Essen
Uwe Schlegel
Department of Neurology, University Hospital Knappschaftskrankenhaus, Ruhr-Universität Bochum
Oliver Grauer
Department of Neurology, University of Münster
Dietmar Krex
Department of Neurosurgery, University of Dresden
Oliver Schnell
Department of Neurosurgery, University of Freiburg
Roland Goldbrunner
Department of Neurosurgery, University of Cologne
Michael Sabel
Department of Neurosurgery, University of Düsseldorf
Niklas Thon
Department of Neurosurgery, Ludwig Maximillian University of Munich and German Cancer Consortium, Partner Site Munich
Daniel Delev
Department of Neurosurgery, University Hospital RWTH Aachen
Hans Clusmann
Department of Neurosurgery, University Hospital RWTH Aachen
Clemens Seidel
Department of Radiotherapy and Radiation Oncology, University of Leipzig
Erdem Güresir
Department of Neurosurgery and Center of Integrated Oncology, University Hospital Bonn
Matthias Schmid
Institute of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn
Patrick Schuss
Department of Neurosurgery and Center of Integrated Oncology, University Hospital Bonn
Frank A. Giordano
Department of Radiation Oncology, University Hospital Bonn
Alexander Radbruch
Department of Neuroradiology, University Hospital Bonn
Albert Becker
Department of Neuropathology, University Hospital Bonn
Johannes Weller
Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn
Christina Schaub
Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn
Hartmut Vatter
Department of Neurosurgery and Center of Integrated Oncology, University Hospital Bonn
Judith Schilling
Clinical Study Core Unit Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, University Bonn
Frank Winkler
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)
Ulrich Herrlinger
Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn
Matthias Schneider
Department of Neurosurgery and Center of Integrated Oncology, University Hospital Bonn
Abstract 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
