Phase 2, Open-label, Single-arm Study on the Use of Metformin as Adjunctive Therapy in High-grade Glioma

Inclusion Criteria:

• Patients with newly diagnosed histologically confirmed GBM (WHO grade IV, IDH wildtype) undergoing surgical resection;

• hypomethylation or hypermethylation of MGMT assessed post-surgery;

• adult patients (≥18 years), both sexes;

• Patients undergoing Stupp protocol including patients aged > 70 years performing thehypofractionated protocol and three weeks of chemotherapy;

• Karnofsky Performance Status (KPS)> 60 assessed post-surgery;

• life expectancy at least 6 months defined by size and location of lesion tumor;

• freely given written informed consent prior to any activity related to the study.Patients must be able to communicate with the investigator and comply with the studyprocedures;

• Women of childbearing age must test negative for pregnancy at enrollment and, ifthey have sexual intercourse, they must agree to use specific contraceptive methods.Female subjects of childbearing age, i.e., fertile, after menarche and untilpost-menopause unless they are permanently infertile, who are sexually active, mustapply a highly effective method of birth control with a low failure rate (i.e., lessthan 1 percent per year), such as combined hormonal contraception (containingestrogen and progestin) combined with ovulation inhibition (oral intravaginal, ortransdermal), progestin-only hormonal contraception associated with ovulationinhibition (oral, injectable, or implantable), intrauterine device (IUD),intrauterine hormone delivery system (IUS), bilateral tubal occlusion, vasectomizedpartner, or sexual abstinence, throughout the treatment period and for four weeksafter the last dose of the study treatment. Hormonal methods other thanlevonorgestrel-containing devices or medroxyprogesterone injections should besupplemented with the use of a male condom. Women of nonfertile age may be includedif surgically sterile or postmenopausal for at least 2 years. The investigator isresponsible for determining whether the patient has adopted an appropriate method ofcontraception for participation in the study.

• Male subjects with female partners of childbearing age must use condoms duringtreatment and until the end of relevant systemic exposure.

Exclusion Criteria:

• Multicenter GBMs;

• Patients diagnosed with diabetes or diabetes-related conditions;

• other active malignancies;

• hypersensitivity, intolerance to metformin or excipients;

• Impaired renal function with creatinine clearance < 60 mL/min assessed atrecruitment, liver failure assessed at recruitment by clinical history andexamination of ALT, AST and total bilirubin, and other contraindications tometformin use;

• taking metformin, insulin or other biguanides, regardless of the reason;

• pregnancy or lactation;

• patient has serious pre-existing medical conditions that, in the opinion of theinvestigator, would preclude participation in this study.