Treatment With Azacitidine of Recurrent Gliomas With IDH1/2 Mutation

Scientific justification:

Gliomas are the most frequent brain tumors. Prognosis is poor. It depends on the histological grade (I to IV), and on the molecular profile, and particularly on the presence of IDH (Isocitrate dehydrogenase) mutation which is associated with a better prognosis. Mutations of IDH1R132, less frequently IDH2R172 affect 40% of gliomas, mostly grade II and grade III. IDH mutation results in the accumulation of D-2 hydroxyglutarate (D2HG) produced by the IDH1 mutant enzyme. D2HG acts as a competitive inhibitor of the alphaketoglutarate cofactor in a wide range of cellular reactions, including TET family enzymes and histone demethylases, resulting in DNA hypermethylation (CpG Island Methylator Phenotype, CIMP) and histone hypermethylation. IDH mutation is probably the earliest genetic alteration in the tumorigenesis of gliomas, and is also the most stable, as shown in a whole exome analysis of initial and recurring low grade gliomas. It is therefore an attractive target. In an attempt to reverse the CIMP status, in vitro and in vivo experiments showed a dramatic anti-tumor effect of hypomethylating drugs (5-azacytidine and 5-deoxyazacytidine) on IDH1 mutated human gliomas . These hypomethylating drugs are routinely used in myelodysplasic syndrome and are well tolerated. Despite glioma with IDH1/2 mutation have a better outcome compared to the IDH wild-type counterpart, the prognosis remains grim with no therapeutic perspective after radiotherapy, temozolomide and/or nitrosourea treatment. Another reason to administer the hypomethylating drug after failure of alkylating chemotherapy is based on the assumption that demethylation of O6-methylguanine-DNA-methyltransferase (MGMT) promoter could compromise the efficacy of future alkylating treatment. Based on preclinical data obtained in animal models and clinical data of patients with MDS, we will treat with demethylating drug (Azacitidine, Vidaza®) patients with recurrent IDH mutated gliomas (as authentificated by IDHR132H Immunochemistry or direct sequencing). Preclinical data on experimental gliomas and clinical data on MDS, has shown that efficacy is delayed by three or more cycles. This has important consequences in the selection of the population, and the follow-up of the treatment. We will exclude patients with important mass effect and intracranial hypertension, and more generally patients whose life expectancy is inferior to 9 months. Despite such treatment has never been evaluated in IDH mutated glioma patients, the biological and preclinical backgrounds are extremely strong and the drug is well tolerated and widely used in the field of haematology.

Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA. The cytotoxic effects of azacitidine may result from multiple mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damage pathways. Non-proliferating cells are relatively insensitive to azacitidine. Incorporation of azacytidine into DNA results in the inactivation of DNA methyltransferases, leading to hypomethylation of DNA.

DNA hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation, differentiation and death pathways may result in gene re-expression and restoration of cancer suppressing functions to cancer cells. The relative importance of DNA hypomethylation versus cytotoxicity or other activities of azacitidine to clinical outcomes has not been established.

Azacitidine is small molecule. Pharmacokinetic data suggest a good penetration in the Central Nervous System (CNS). 5-aza-dCyd, active metabolite of azacitidine, can cross the blood-Cerebro Spinal Fluid (CSF) barrier effectively, producing cytotoxic concentrations in the CSF when given by i.v. infusion in animal models .