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 .
In IDH mutated tumors, it is believed that the inactivation of tumor suppressor genes by
aberrant DNA methylation of CpG islands plays an important role in the development of
malignancy. DNA methylation usually occurs at the 5-position of the cytosine ring within
cytosine-phosphate-guanine (CpG) dinucleotide by a transfer of the methyl group from
S-adenosyl-L-methionine. Azacitidine reactivates many tumor suppressor genes that are
aberrantly silenced in hypermethylated tumors, including Rb, p53, CDKN2A, and mismatch repair
genes which are involved in alkylating resistance. It may also reactivate MGMT, which makes
the cell more sensitive to alkylating drugs: this may be a deleterious effect. This is one
more reason to reserve this treatment to patients previously treated with alkylating drugs
which developed secondary resistance: one of the mechanisms of resistance is the inactivation
of mismatch repair genes which occurs after alkylating treatment and is a mechanism of
secondary resistance in MGMT promoter methylated gliomas. Re-expressing these genes may
render the tumor more sensitive to chemotherapy.
Description and justification of the dosage, route of administration, administration schedule
and treatment duration:
Vidaza® is approved by the European Commission for the treatment of adult patients who are
not eligible for haematopoietic stem cell transplantation (HSCT) with: intermediate-2 and
high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring
System (IPSS),, chronic myelomonocytic leukaemia (CMML) with 10-29 % marrow blasts without
myeloproliferative disorder, acute myeloid leukaemia (AML) with 20-30 % blasts and
multi-lineage dysplasia, according to World Health Organization (WHO) classification, AML
with >30% marrow blasts according to the WHO classification.
In these approved indications, the recommended starting dose for the first treatment cycle,
for all patients regardless of baseline haematology laboratory values, is 75 mg/m2 of body
surface area, injected subcutaneously, daily for 7 days, followed by a rest period of 21 days
(28-day treatment cycle) every 4 weeks until progression, intolerance or end of the study. It
is recommended that patients be treated for a minimum of 6 cycles. In absence of study in
neuro-oncology, it was decided to use same dosage and schedule as in haematological
malignancies.
Summary of the known and foreseeable benefits and risks for the study participants:
In this population, there is currently no available treatment, shown to have any efficacy.
Despite there is no data on efficacy of azacitidine in this population there is a strong
biological and preclinical background. Furthermore the tolerance is well known since the drug
is widely used in hematology. The toxicity is mostly haematologic and renal and easily
manageable. However there are two caveats:
- Since the response is delayed, we expect no effect before 3 cycles. Moreover
neurological worsening must be expected and anticipated and treated if necessary by
introducing or increasing steroids.
- Demethylation modifies gene expression and reactivates tumor suppressor genes; however
we cannot not exclude a deleterious effect (ie reactivation of deleterious genes). This
is a theoretical risk though it has not been reported in the MDS and AML treated with
azacitidine.
Objectives and endpoints:
The primary objective of this study will be to evaluate the efficacy based on RANO criteria,
of azacitidine in patients with recurrent IDH1/2 mutated glioma after conventional
treatments. The primary assessment criterion will be Progression-Free Survival at 6 months
(PFS-6) (24 weeks) estimated by the RANO criteria.
The Secondary objectives will be 1/ to evaluate the clinical efficacy: objective response
rate after 6 cycles of treatment evaluated by RANO criteria and overall survival, 2/ to
evaluate the safety and tolerability of azacitidine by description and graduation of adverse
events according to the revised NCI Common Terminology Criteria for Adverse Events (CTCAE
V4.0).
Design of the Study:
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 IDH1/2 mutant gliomas.
Statistical aspects:
A Fleming two-stage design is used to assess the efficacy of Azacitidine on the 6-months
progression free survival. Minimal efficacy (p0) and expected efficacy (p1) are respectively
fixed to 15% and 30%. With a type I error rate of 5%, and an 80% power, 19 patients are
required for the first step, and 36 additional patients for the second step if no conclusion
has been reached at intermediate analysis. In this configuration we plan to enroll 63
patients in order to have 55 patients who will receive at least 1 cycle of treatment.
Inclusion Criteria:
- Age > 18 years
- Glioma grade II or III with IDH1 or IDH2 mutation
- Recurring after standard treatment, ie radiotherapy and alkylating chemotherapy, or
alkylating chemotherapy alone in case of gliomatosis cerebri
- For the patients treated by radiotherapy, recurrence occurring more than three months
from the end of the radiotherapy or occurring outside the irradiated volume
- Karnofsky Performance Status > 50
- Life expectancy > 9 months
- Living within the geographic perimeter of the APHP (Assistance Publique - Hôpitaux de
Paris) home hospitalization center (departments 75, 92, 93, 94)
- Suitable laboratory values obtained ≤ 7 days before inclusion visit:
- Absolute neutrophil count (ANC) ≥ 1500 /mm3
- Leucocytes ≥ 3,0 x 109/L
- Platelet count ≥ 75 000 / mm3
- Hemoglobin > 9.0 g/dL
- Serum GlutamoOxaloacetate Transferase (SGOT) (AST) ≤ 3 x Upper Limit of Normal
(ULN)
- Serum Glutamate Pyruvate Transaminase (SGPT) (ALT) ≤ 3 x ULN
- Uremia ≤ 1.5 x ULN
- Creatininemia ≤ 1.5 x ULN
- Bicarbonates ≥ 22 mmol/l
- Women of child-bearing potential (i.e. women who are pre-menopausal or not surgically
sterile) must :
- Have a negative serum or urine pregnancy test within 2 weeks prior to beginning
treatment on this study.
- Agree to use, and to be able to comply with, effective contraception without
interruption, throughout the entire duration study drug therapy (including doses
interruptions) and for 3 months after the end of the study drug therapy.
- Male patients :
- must agree to use a condom if engaged in sexual activity with a woman of
childbearing potential during the entire period of treatment and during 3 months
after end of treatment.
- are informed about the procedures for preservation of sperm before starting
treatment.
- Written informed consent dated and signed, prior to any study specific procedures
(sampling, treatment and analyses).
- Affiliation to the French health insurance (recipient or assign)
Exclusion Criteria:
- Breast-feeding women
- Any evidence of severe or uncontrolled systemic diseases (as judged by the
investigator), including uncontrolled hypertension, active bleeding diatheses, or
active infection including hepatitis B, hepatitis C and human immunodeficiency virus
(HIV) (Screening for chronic conditions is not required)
- Active pulmonary disease or congestive cardiac insufficiency
- Malignant hepatic tumor at a later stage
- Intracranial hypertension or important deviation of the midline on the MRI
- Any investigational agents or study drugs from a previous clinical study (within 30
days before the first dose of study treatment
- Any chemotherapy, anticancer immunotherapy or anticancer agents within 4 weeks (6
weeks for nitrosourea) before the first dose of study treatment
- Any unresolved toxicities (excepted alopecia), from prior therapy greater than CTCAE
grade 1 at the time of inclusion
- Known hypersensitivity to Azacitidine or Mannitol (E421), (refer to the Investigator's
Brochure)
- Patients under curatorship or guardianship