Journal Article

DKFZ-2022-00212

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy-the MecMeth/NOA-24 trial.

Zeyen, T. ; Potthoff, A.-L. ; Nemeth, R. ; Heiland, D. H. ; Burger, M. C. ; Steinbach, J. P. ; Hau, P. ; Tabatabai, G. ; Glas, M. ; Schlegel, U. ; Grauer, O. ; Krex, D. ; Schnell, O. ; Goldbrunner, R. ; Sabel, M. ; Thon, N.DKFZ* ; Delev, D. ; Clusmann, H. ; Seidel, C. ; Güresir, E. ; Schmid, M. ; Schuss, P. ; Giordano, F. A. ; Radbruch, A. ; Becker, A. ; Weller, J. ; Schaub, C. ; Vatter, H. ; Schilling, J. ; Winkler, F.DKFZ* ; Herrlinger, U. ; Schneider, M.

2022
BioMed Central London

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Please use a persistent id in citations: doi:10.1186/s13063-021-05977-0

Abstract: 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.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.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.EudraCT 2021-000708-39 . Registered on 08 February 2021.

Keyword(s): Antineoplastic Agents, Alkylating: adverse effects (MeSH) ; DNA Modification Methylases: therapeutic use (MeSH) ; DNA Repair Enzymes: genetics (MeSH) ; DNA Repair Enzymes: therapeutic use (MeSH) ; Glioblastoma: drug therapy (MeSH) ; Glioblastoma: genetics (MeSH) ; Humans (MeSH) ; Meclofenamic Acid: therapeutic use (MeSH) ; Neoplasm Recurrence, Local (MeSH) ; Temozolomide: adverse effects (MeSH) ; Tumor Suppressor Proteins: therapeutic use (MeSH) ; Glioblastoma ; Meclofenamate ; Relapse ; Second-line therapy ; Temozolomide ; Antineoplastic Agents, Alkylating ; Tumor Suppressor Proteins ; Meclofenamic Acid ; DNA Modification Methylases ; MGMT protein, human ; DNA Repair Enzymes ; Temozolomide

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Contributing Institute(s):

1. KKE Neuroonkologie (B320)
2. DKTK HD zentral (HD01)
3. DKTK MU LMU zentral (MU01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2022

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