Neoplasms

All Conditions

Rare Diseases

Glioblastoma

Glioma

Astrocytoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Hypoglycemic Agents

All Drugs and Chemicals

Antineoplastic Agents

Metformin

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients who have been selected with an OXPHOS+ status, will start standard radiotherapy (RT, 60Gy/6 weeks), concomitant TMZ chemotherapy (75mg/m²/day), and metformin by 7 weeks after surgery and adjuvant TMZ + metformin will follow onwards until the 12th cycle of TMZ. Patients still in remission after this time-point will continue metformin alone until progression.

Metformin 2000 to 3000mg/day daily will be started by 6 weeks after histological diagnosis and 7 days before the start of RT-TMZ and will continue until progression.

2 Gy x 5 days for 6 weeks to be started 7 days after first administration of Metformin and by 7 weeks after histological diagnosis

Radiation IMRT

75 mg/m² daily from first to last day of radiation (IMRT) and then 150 to 200 mg/m² x 5 days every 28 days cycle for 12 cycles

Anna Luisa DI STEFANO, MD

Elisabeth HULIER-AMMAR, PhD

François DUCRAY, PUPH

Olivier CHINOT, PUPH

Antoine CARPENTIER, PUPH

Marc SANSON, PUPH

Marica EOLI, MD

Tailored approaches targeting crucial oncogenes and pathways have shown successful results in a number of cancer types and offer exciting perspective in neuro-oncology. IDH (Isocitrate dehydrogenase) wild-type (IDHwt) glioblastoma (GBM) (10%) present a unique and homogenous energetic metabolism which is specifically dependent on the oxidative phosphorylation (OXPHOS) rather than on the aerobic glycolysis. OXPHOS+ IDHwt GBMs overexpress mitochondrial markers and can be specifically inhibited by mitochondrial inhibitors in vitro and in vivo.

Metformin is an oral inhibitor of mitochondrial complex I and is a widely used drug in diabetic and non-diabetic patients, safe and well tolerated in association with radiotherapy and chemotherapy.

Basing on drastic effect, the investigators have observed in vivo (reduction of \>50% of tumor growth) and hypothesize that metformin could be specifically efficient to treat up-front patients affected by OXPHOS+ GBM, in association with the standard first-line treatment with radiotherapy and temozolomide (RT-TMZ).

The investigators set up a dedicated molecular analysis including RNA assay and expression of OXPHOS markers for formalin-fixed paraffin-embedded tumors (FFPE), which allows to detect OXPHOS+ GBM at diagnosis.

Here a phase II, open label, non-randomized multicenter trial including five French neurooncology centers (H. Foch-Suresnes, Pitié-Salpêtrière-Paris, Saint Louis-Paris, Lyon, Marseille) and one in Italy (Istituto Besta, Milan) is proposed.

Newly diagnosed IDH wild-type GBM patients with the OXPHOS+ signature will be eligible for inclusion in this trial. The investigators expect to screen 640 patients and to include 64 patients over a period of 24 months with 24 months of follow-up.

Metformin (1500 to 3000mg/day) in addition to Stupp protocol, starting 7 days before the start of the standard radiotherapy (RT, 60Gy/6 weeks), concomitant Temozolomide (TMZ) chemotherapy (75mg/m²/day), and adjuvant TMZ (150-200 mg/m2/ 5 days) + metformin will follow onwards until the 12th cycle of TMZ

Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide

Progression free survival (PFS) estimated by the RANO (Response Assesment in Neuro Oncology) criteria

Overall response rate (ORR) estimated by the RANO criteria

Type, frequency, and severity (grade III and IV toxicity) of Adverse Events (AEs) and Serious Adverse Events (SAEs)

Dose interruptions, reductions and dose intensity.

Spots Global Cancer Trial Database for radiation imrt