A phase Ib/II randomized, open-label drug repurposing trial of glutamate signaling inhibitors in combination with chemoradiotherapy in patients with newly diagnosed glioblastoma: the GLUGLIO trial protocol

Background Glioblastoma is the most common and most aggressive malignant primary brain tumor in adults. Glioblastoma cells synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Moreover, neuronal networks in...

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Vydáno v:	BMC cancer Ročník 24; číslo 1; s. 82 - 7
Hlavní autoři:	Mastall, Maximilian, Roth, Patrick, Bink, Andrea, Fischer Maranta, Angela, Läubli, Heinz, Hottinger, Andreas Felix, Hundsberger, Thomas, Migliorini, Denis, Ochsenbein, Adrian, Seystahl, Katharina, Imbach, Lukas, Hortobagyi, Tibor, Held, Leonhard, Weller, Michael, Wirsching, Hans-Georg
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 15.01.2024 BioMed Central Ltd Springer Nature B.V BMC
Témata:	Adult Amino acids Analysis Antibiotics Anticonvulsants Biomedical and Life Sciences Biomedicine Brain cancer Brain Neoplasms - drug therapy Brain Neoplasms - genetics Brain tumors Calcium signalling Cancer neuroscience Cancer Research Cancer therapies Care and treatment Caregivers Chemoradiotherapy Chemotherapy Clinical Trials, Phase I as Topic Clinical Trials, Phase II as Topic Cognitive ability Convulsions & seizures Diagnosis DNA methylation DNA methyltransferase Dosage and administration Drug development Drug dosages Drug Repositioning EEG Electroencephalography Epilepsy Gabapentin Gap junctions Glioblastoma Glioblastoma - drug therapy Glioblastoma - genetics Glioblastoma cells Glioblastoma multiforme Glutamate Glutamatergic transmission Glutamates Health Promotion and Disease Prevention Humans Magnetic resonance imaging Magnetic resonance spectroscopy Medicine/Public Health Memantine Methylation Methylguanine Multicenter Studies as Topic Neural networks Neuroimaging Neurons Nuclear magnetic resonance spectroscopy O6-methylguanine-DNA methyltransferase Oncology Patients Quality of Life Questionnaires Radiation therapy Randomized Controlled Trials as Topic Seizures Seizures (Medicine) Standard of care Steroids - therapeutic use Study Protocol Sulfasalazine Surgical Oncology Synapses Temozolomide Testing Toxicity Tumor cells Switzerland Cancer neuroscience Sulfasalazine Memantine Gabapentin Epilepsy
ISSN:	1471-2407, 1471-2407
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Shrnutí:	Background Glioblastoma is the most common and most aggressive malignant primary brain tumor in adults. Glioblastoma cells synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Moreover, neuronal networks interconnect with glioblastoma cell networks through glutamatergic neuroglial synapses, activation of which induces oncogenic calcium oscillations that are propagated via gap junctions between tumor cells. The primary objective of this study is to explore the efficacy of brain-penetrating anti-glutamatergic drugs to standard chemoradiotherapy in patients with glioblastoma. Methods/design GLUGLIO is a 1:1 randomized phase Ib/II, parallel-group, open-label, multicenter trial of gabapentin, sulfasalazine, memantine and chemoradiotherapy (Arm A) versus chemoradiotherapy alone (Arm B) in patients with newly diagnosed glioblastoma. Planned accrual is 120 patients. The primary endpoint is progression-free survival at 6 months. Secondary endpoints include overall and seizure-free survival, quality of life of patients and caregivers, symptom burden and cognitive functioning. Glutamate levels will be assessed longitudinally by magnetic resonance spectroscopy. Other outcomes of interest include imaging response rate, neuronal hyperexcitability determined by longitudinal electroencephalography, Karnofsky performance status as a global measure of overall performance, anticonvulsant drug use and steroid use. Tumor tissue and blood will be collected for translational research. Subgroup survival analyses by baseline parameters include segregation by age, extent of resection, Karnofsky performance status, O 6 -methylguanine DNA methyltransferase (MGMT) promotor methylation status, steroid intake, presence or absence of seizures, tumor volume and glutamate levels determined by MR spectroscopy. The trial is currently recruiting in seven centers in Switzerland. Trial registration NCT05664464. Registered 23 December 2022.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Undefined-1 ObjectType-Feature-3 content type line 23
ISSN:	1471-2407 1471-2407
DOI:	10.1186/s12885-023-11797-z