Recurrent IDH1/2 Mutated Glioma clinical trials

Treatment With Azacitidine of Recurrent Gliomas With IDH1/2 Mutation

Glioma are the most commun frequent brain tumour. Mutation of Isocitrate DeHydrogenase IDH1 or IDH2 genes affect 40% of gliomas, mostly grade II and III gliomas. Despite IDH mutated gliomas (IDHm glioma) have a better prognosis compared to the IDH wild type counterparts, they invariably recur after standard treatment with radiotherapy and alkylating agent. IDH mutation results in the accumulation of D-2 hydroxyglutarate (D2HG) produced by the IDH mutant enzyme. D2HG acts as a competitive inhibitor of the alphaketoglutarate cofactor in a wide range of cellular reactions, including Ten-eleven translocation (TET) family enzymes and histone demethylases, resulting in DNA hypermethylation (CIMP phenotype) and histone hypermethylation. Preclinical data have shown a dramatic anti-tumor effect of hypomethylating drugs as 5-azacytidine on IDH1 mutated human gliomas. These hypomethylating drugs are routinely used in myelodysplasic syndrome (MDS) and are well tolerated. The AGIR Trial will be a phase II, non-comparative, open label, non randomised monocentric trial evaluating efficacy of a treatment by azacitidine in recurrent IDHm gliomas. The main objective is to evaluate the efficacy of azacitidine according to the RANO criteria on progression-free survival at 6 months, evaluated according to the RANO criteria. Given the slow mode of action of treatment, it is proposed to include only patients whose life expectancy at inclusion is greater than 9 months. A 6-month progression-free survival of less than 15% will be inefficient. The minimum efficiency must be at least 30%. An interim analysis (according to Fleming's method) will be performed when 19 patients have been included and followed up to 6 months. If the interim analysis is inconclusive, 36 additional patients will be included. The maximum number of analysable patients to include is 55.