Using Metformin with Radiotherapy and Temozolomide for Glioblastoma Treatment

Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide

This study is testing if adding metformin to standard treatments of radiotherapy and temozolomide can help people with a specific type of newly diagnosed glioblastoma grow their tumors slower.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 640 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Hopital Foch (other)
• Drugs / interventions: chemotherapy, prednisone
• Locations: 7 sites (Suresnes, Hauts de Seine and 6 other locations)
• Trial ID: NCT04945148 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the effectiveness of metformin, a mitochondrial complex I inhibitor, in combination with radiotherapy and temozolomide for treating newly diagnosed IDH-wildtype glioblastoma. The study focuses on patients with a specific subtype of glioblastoma that relies on oxidative phosphorylation for energy. By targeting this unique metabolic pathway, the researchers aim to reduce tumor growth significantly. The trial will assess the safety and efficacy of this treatment approach in a controlled setting.

Who should consider this trial

Good fit: Ideal candidates include patients with newly diagnosed, histologically confirmed IDH-wildtype glioblastoma who have not received prior treatment other than surgery.

Not a fit: Patients with glioblastoma who have received prior treatments or have significant ongoing safety issues may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with a challenging form of glioblastoma.

How similar studies have performed: Other studies have shown promising results using similar metabolic targeting approaches in cancer treatment, suggesting potential for success in this trial.

Eligibility criteria

Inclusion Criteria:

1. Provision of signed informed consent for selection and treatment phase obtained from the patient/legal representative prior to performing any protocol-related procedures,
2. 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,
3. Newly-diagnosed histologically-confirmed supra-tentorial IDHwt glioblastoma (Grade 4 malignant glioma by World Health Organization, including gliosarcoma),
4. OXPHOS+ subtype by the central laboratory
5. No prior treatment for GBM other than surgery,
6. Substantial recovery from surgical resection, no major ongoing safety issues (eg, infection requiring I.V. antibiotics) following surgery,
7. Without corticosteroids or with stable dose of corticosteroids (ie ≤ dexamethasone 6 mg, methylprednisolone 30 mg or prednisone 38 mg),
8. ECOG (Eastern Cooperative Oncology Group) performance status 0-2,
9. Able to receive concomitant radio-chemotherapy according to the Stupp protocol (60Gy) based on investigator judgment,
10. Adequate bone marrow and normal hepatic function,
11. Creatinine clearance ≥ 30 mL/min (between 30 and 50 ml/min, patients will be prescribed no more than 1500mg of metformin),
12. Able to start RT within 7 weeks after histological diagnosis,
13. Patients must have life expectancy ≥ 16 weeks,
14. Patients affiliated to an appropriate health insurance system,
15. Age ≥ 18 years old,
16. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to the start of study drug,
17. Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception from the signing of the informed consent and continue throughout period of taking study treatment and for 30 days after last dose of study drug (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half-lives (both TMZ and metformin). The terminal half-life of temozolomide is 1.8 hours. The terminal half-life for metformin is 6.5 hours.
18. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception throughout the period of taking study treatment and for 6 months plus the time required for the investigational drug to undergo five half-lives (both TMZ and metformin). The terminal half-life of temozolomide is 1.8 hours. The terminal half-life for metformin is 6.5 hours.
19. White blood cells (WBC) ≥ 2000/μL
20. Neutrophils ≥ 1500/μL,
21. Platelets ≥ 100 x103/μL,
22. Hemoglobin ≥ 9.0 g/dL,
23. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 30 mL/min (using the Cockcroft-Gault formula) Female CrCl = (140-age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140-age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL
24. Aspartate AminoTransferase (AST) ≤ 3.0 x ULN,
25. Alanine Aminotransferase (ALT) ≤ 3.0 x ULN,
26. Total Bilirubin ≤ 1.5 x ULN (except patients with Gilbert Syndrome who may have a total bilirubin \< 3.0 x ULN).

Exclusion Criteria:

1. Prior treatment for GBM (other than surgical resection) including Gliadel wafer,
2. 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,
3. Any known metastatic extracranial or leptomeningeal disease,
4. IDH mutant,
5. Secondary GBM (ie, progression from prior low-grade or anaplastic glioma),
6. 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,
7. 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),
8. Pregnant or breast-feeding women,
9. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving anti-viral therapy,
10. Patients with known active hepatitis (i.e., Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV)),
11. Patients with a known hypersensitivity to metformin and temozolomide or any of the excipients of the products,
12. Patients with severe renal insufficiency ie, CrCl \< 30 mL/min (who should not receive contrast materials),
13. 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,
14. Patients unable (eg, due to pacemaker or Implantable Cardioverter Defibrillator (ICD) device) or unwilling to have a contrast-enhanced MRI of the head,
15. Any acute medical condition that may impair renal function such as dehydration, severe infection, shock,
16. Any disease which may cause tissue hypoxia such as decompensated heart failure, respiratory failure, recent myocardial infarction
17. Past Diabetic precoma
18. Past Acute metabolic acidosis,
19. Alcohol intoxication and Alcoholism,
20. Persons protected by a legal regime (guardianship, trusteeship),
21. Prisoners or patients who are involuntarily incarcerated,
22. Patients who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

Where this trial is running

Suresnes, Hauts de Seine and 6 other locations

• Foch Hospital — Suresnes, Hauts de Seine, France (RECRUITING)
• Hôpital Neurologique Pierre Wertheimer — Bron, Lyon, France (RECRUITING)
• Timone Hospital — Marseille, Marseille, France (RECRUITING)
• Saint Louis Hospital — Paris, Paris, France (RECRUITING)
• Pitié Salpêtrière Hospital — Paris, PARIS, France (RECRUITING)
• Istituto Nazionale Carlo Besta — Milan, Milano, Italy (NOT_YET_RECRUITING)
• Spidali Riuniti Di Livorno — Livorno, Toscana Nord Ouest, Italy (NOT_YET_RECRUITING)

Study contacts

• Principal investigator: Anna Luisa DI STEFANO, MD — Foch Hospital
• Study coordinator: Anna Luisa DI STEFANO, MD

Conditions: Glioblastoma, IDH-wildtype, Glioblastoma, FGFR3-TACC3, Metformin, Radio-chemotherapy, OXPHOS+