1. Marizomib for patients with newly diagnosed glioblastoma: A randomized phase 3 trial
- Author
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Roth, Patrick, Gorlia, Thierry, Reijneveld, Jaap C, de Vos, Filip, Idbaih, Ahmed, Frenel, Jean-Sébastien, Le Rhun, Emilie, Sepulveda, Juan Manuel, Perry, James, Masucci, G Laura, Freres, Pierre, Hirte, Hal, Seidel, Clemens, Walenkamp, Annemiek, Lukacova, Slavka, Meijnders, Paul, Blais, Andre, Ducray, Francois, Verschaeve, Vincent, Nicholas, Garth, Balana, Carmen, Bota, Daniela A, Preusser, Matthias, Nuyens, Sarah, Dhermain, Fréderic, van den Bent, Martin, O’Callaghan, Chris J, Vanlancker, Maureen, Mason, Warren, and Weller, Michael
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Clinical Trials and Supportive Activities ,Rare Diseases ,Neurosciences ,Comparative Effectiveness Research ,Brain Cancer ,Patient Safety ,Clinical Research ,Radiation Oncology ,Cancer ,Brain Disorders ,6.1 Pharmaceuticals ,Humans ,Glioblastoma ,Male ,Middle Aged ,Female ,Brain Neoplasms ,Aged ,Lactones ,Adult ,Temozolomide ,Pyrroles ,Survival Rate ,DNA Repair Enzymes ,Follow-Up Studies ,DNA Modification Methylases ,Chemoradiotherapy ,Prognosis ,Antineoplastic Combined Chemotherapy Protocols ,Young Adult ,EORTC 1709 ,glioma ,MGMT ,proteasome inhibitor ,randomized study ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundStandard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier.MethodsEuropean Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors.ResultsThe trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm.ConclusionsAdding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.
- Published
- 2024