Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide

NCT04945148 | Recruiting Phase 2

• 1 other identifier: 2019_0007
• Study Type: interventional
• Target: 640
• Locations: 2 countries
• Sites: 7

Brief Summary

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.

Conditions

Glioblastoma, IDH-wildtype

Keywords

Glioblastoma; FGFR3-TACC3; Metformin; Radio-chemotherapy; OXPHOS+

Outcome Measures

Primary Outcomes (1)

• Assessement of Progression Free Survival (PFS) of patients with newly-diagnosed IDH wild-type OXPHOS + GBM (either with or without FGFR3-TACC3 gene fusion) treated with RT plus TMZ combined with metformin

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

  During the 24 months of follow-up

Secondary Outcomes (4)

• Assessement of the Overall survival (OS) of treated patients

  During the 24 months of follow-up

• Assessement of the Overall Response rate (ORR)

  During the 24 months of follow-up

• Assessement of the the safety of metformin in association with concomitant RT-TMZ

  During the 24 months of follow-up

• Assessement of the the tolerability of metformin in association with concomitant RT-TMZ

  During the 24 months of follow-up

Study Arms (1)

Metformin

EXPERIMENTAL

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.

Drug: Metformin; Radiation: Radiation IMRT; Drug: Temozolomide

Interventions

Metformin DRUG

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.

Metformin

Radiation IMRT RADIATION

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

Also known as: Radiation

Metformin

Temozolomide DRUG

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

Metformin

Eligibility Criteria

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

You may qualify if:

• Provision of signed informed consent for selection and treatment phase obtained from the patient/legal representative prior to performing any protocol-related procedures,
• Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits, and examinations including follow-up,
• Newly-diagnosed histologically-confirmed supra-tentorial IDHwt glioblastoma (Grade 4 malignant glioma by World Health Organization, including gliosarcoma),
• OXPHOS+ subtype by the central laboratory
• No prior treatment for GBM other than surgery,
• Substantial recovery from surgical resection, no major ongoing safety issues (eg, infection requiring I.V. antibiotics) following surgery,
• Without corticosteroids or with stable dose of corticosteroids (ie ≤ dexamethasone 6 mg, methylprednisolone 30 mg or prednisone 38 mg),
• ECOG (Eastern Cooperative Oncology Group) performance status 0-2,
• Able to receive concomitant radio-chemotherapy according to the Stupp protocol (60Gy) based on investigator judgment,
• Adequate bone marrow and normal hepatic function,
• Creatinine clearance ≥ 30 mL/min (between 30 and 50 ml/min, patients will be prescribed no more than 1500mg of metformin),
• Able to start RT within 7 weeks after histological diagnosis,
• Patients must have life expectancy ≥ 16 weeks,
• Patients affiliated to an appropriate health insurance system,
• Age ≥ 18 years old,

You may not qualify if:

• Prior treatment for GBM (other than surgical resection) including Gliadel wafer,
• Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years,
• Any known metastatic extracranial or leptomeningeal disease,
• IDH mutant,
• Secondary GBM (ie, progression from prior low-grade or anaplastic glioma),
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the patient to receive protocol therapy, or interfere with the interpretation of study results,
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication (inflammatory bowel disease, major bowel resection),
• Pregnant or breast-feeding women,
• Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving anti-viral therapy,
• Patients with known active hepatitis (i.e., Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV)),
• Patients with a known hypersensitivity to metformin and temozolomide or any of the excipients of the products,
• Patients with severe renal insufficiency ie, CrCl \< 30 mL/min (who should not receive contrast materials),
• History or evidence upon physical/neurological examination of other central nervous system condition (eg, seizures, abscess) unrelated to cancer, unless adequately controlled by medication or considered not potentially interfering with protocol treatment,
• Patients unable (eg, due to pacemaker or Implantable Cardioverter Defibrillator (ICD) device) or unwilling to have a contrast-enhanced MRI of the head,
• Any acute medical condition that may impair renal function such as dehydration, severe infection, shock,

Sponsors & Collaborators

• Hopital Foch: lead
• National Cancer Institute, France: collaborator

Study Sites (7)

Foch Hospital

Suresnes, Hauts de Seine, 92150, France

RECRUITING

Hôpital Neurologique Pierre Wertheimer

Bron, Lyon, 69500, France

RECRUITING

Timone Hospital

Marseille, Marseille, 13354, France

RECRUITING

Saint Louis Hospital

Paris, Paris, 75010, France

RECRUITING

Pitié Salpêtrière Hospital

Paris, PARIS, 75013, France

RECRUITING

Istituto Nazionale Carlo Besta

Milan, Milano, 20131, Italy

NOT YET RECRUITING

Spidali Riuniti Di Livorno

Livorno, Toscana Nord Ouest, 57100, Italy

NOT YET RECRUITING

MeSH Terms

Conditions

Glioblastoma

Interventions

Metformin; Radiation; Temozolomide

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Physical Phenomena; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Anna Luisa DI STEFANO, MD

  Foch Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anna Luisa DI STEFANO, MD

CONTACT

01 46 25 37 22; al.di-stefano@hopital-foch.com

Elisabeth HULIER-AMMAR, PhD

CONTACT

01 46 25 11 75; drci-promotion@hopital-foch.com

Study Design

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

Model Details: 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

Study Record Dates

• First Submitted: June 25, 2021
• First Posted: June 30, 2021
• Study Start: May 10, 2024
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2028
• Last Updated: November 21, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

FR (5); IT (2)