Treatment With Azacitidine of Recurrent Gliomas With IDH1/2 Mutation

NCT03666559 | Active Not Recruiting Phase 2

• 2 other identifiers: P140910J2016-002822-35
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Recurrent IDH1/2 Mutated Glioma

Keywords

Glioma; IDH1/2; Azacitidine; PFS

Outcome Measures

Primary Outcomes (1)

• Progression-Free Survival at 6 months (PFS-6)

  Evaluation of the efficacy based on Radiologic Assessment in Neuro-Oncology (RANO) criteria,

  at Month 6 after first administration of the drug

Secondary Outcomes (3)

• Incidence of Treatment-Emergent Adverse Events (safety and tolerability)

  During all the study until 1 Month after the last administration of the drug

• Overall Response rate at 6 months

  At the end of Cycle 6 (each cycle is 28 days)

• Overall survival (OS)

  Through study completion up to 42 months

Study Arms (1)

Azacitidine

EXPERIMENTAL

Azacitidine 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.

Drug: Azacitidine

Interventions

Azacitidine DRUG

Chemotherapy

Also known as: Vidaza

Azacitidine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 18 years
• Glioma grade II or III with IDH1 or IDH2 mutation
• Recurring after standard treatment, ie radiotherapy and at least one 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
• 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
• 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 :

You may not qualify if:

• 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
• Known hypersensitivity to Azacitidine or Mannitol (E421), (refer to the Investigator's Brochure)
• Patients under curatorship or guardianship

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Pitie Salpetriere Hospital

Paris, 75013, France

Location

MeSH Terms

Conditions

Glioma

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Caroline DEHAIS, MD

  Hospital Pitié-Salpêtrière, Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2018
• First Posted: September 12, 2018
• Study Start: September 22, 2020
• Primary Completion: February 23, 2023
• Study Completion: March 23, 2024
• Last Updated: February 29, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• Access Criteria: Researchers who provide a methodologically sound proposal.

Locations

FR (1)