Clinical Trials /

Treatment With Azacitidine of Recurrent Gliomas With IDH1/2 Mutation

NCT03666559

Description:

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.

Related Conditions:
  • WHO Grade II Glioma
  • WHO Grade III Glioma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Treatment With Azacitidine of Recurrent Gliomas With IDH1/2 Mutation
  • Official Title: Treatment With Azacitidine of Recurrent Gliomas With IDH1/2 Mutation

Clinical Trial IDs

  • ORG STUDY ID: P140910J
  • SECONDARY ID: 2016-002822-35
  • NCT ID: NCT03666559

Conditions

  • Recurrent IDH1/2 Mutated Glioma

Interventions

DrugSynonymsArms
AzacitidineVidazaAzacitidine

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
AzacitidineExperimentalAzacitidine is administered by sub-cutaneous injection at 75 mg/m2 per day for seven consecutive days every 4 weeks until progression, intolerance or end of the study.
  • Azacitidine

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival at 6 months (PFS-6)
Time Frame:at Month 6 after first administration of the drug
Safety Issue:
Description:Evaluation of the efficacy based on Radiologic Assessment in Neuro-Oncology (RANO) criteria,

Secondary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events (safety and tolerability)
Time Frame:During all the study until 1 Month after the last administration of the drug
Safety Issue:
Description:Incidence of each adverse events and serious adverse events and graduation according to the revised NCI Common Terminology Criteria for Adverse Events (CTCAE V4.0).
Measure:Overall Response rate at 6 months
Time Frame:At the end of Cycle 6 (each cycle is 28 days)
Safety Issue:
Description:Objective response rate (partial response (PR) and complete response (CR) to total treatment duration for 6 months, or until progressive disease, unacceptable toxicity or withdrawal of consent.
Measure:Overall survival (OS)
Time Frame:Through study completion up to 42 months
Safety Issue:
Description:OS is defined as the number of days from the date of the first dose of azacitidine to the date of death due to any cause.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Assistance Publique - Hôpitaux de Paris

Trial Keywords

  • Glioma
  • IDH1/2
  • Azacitidine
  • PFS

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