Clinical trial NCT05929495: Phase 2, Open-label, Single-arm Study on the Use of Metformin as Adjunctive Therapy in High-grade Glioma
Official title: Phase 2, Open-label, Single-arm Study on the Use of Metformin as Adjunctive Therapy in High-grade Glioma
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Glioblastoma, IDH-wildtype
Metformin
Malignancies
Keywords: Metformin
Gliomas
GBM
Lead sponsor: University of Milano Bicocca
Sponsor class: OTHER
First posted: 2023-07-03
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Metformin dose of 1 g/day orally in two administrations (500 mg tablets) during the first two weeks of treatment, increasing to 2 g/day in two 1 g tablets thereafter
Primary purpose: TREATMENT

Brief summary: About 75% of CNS malignant tumors are classified as gliomas and the IDH-wildtype glioblastoma (GBM) represents the most aggressive form among CNS malignancies.

This is a nationwide single-center phase II drug clinical trial with an approximate duration of 32 months.

The clinical trial will be single-arm to evaluate the biological activity and effects of metformin in combination with TMZ in patients with GBM.

Detailed description: About 75% of CNS malignant tumors are classified as gliomas, tumors of neuroectodermal origin arising from glial cells or glial cell precursors. The World Health Organization classification distinguishes gliomas into low-grade gliomas (low-grade gliomas, grade I and II) and high-grade gliomas (high-grade gliomas, grade III and IV).

IDH-wildtype glioblastoma (GBM) represents the most aggressive form among CNS malignancies.

Over the past century, numerous epidemiological and experimental observations have reported a preventive and beneficial antitumor effect of metformin, which has suggested the possibility of using it as adjunctive therapy in many cancer subtypes, including GBM.

The aim of this study is to evaluate the effect of Metformin as adjuvant therapy to TMZ in the treatment of patients with GBM.

Patients will start with a Metformin dose of 1 g/day orally in two administrations (500 mg tablets) during the first two weeks of treatment, increasing to 2 g/day in two 1 g tablets thereafter.

The approximate total duration of the study is 32 months, and 25 patients will be enrolled

Eligibility criteria: Inclusion Criteria:

* Patients with newly diagnosed histologically confirmed GBM (WHO grade IV, IDH wild type) 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 the hypofractionated 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 study procedures;
* Women of childbearing age must test negative for pregnancy at enrollment and, if they have sexual intercourse, they must agree to use specific contraceptive methods. Female subjects of childbearing age, i.e., fertile, after menarche and until post-menopause unless they are permanently infertile, who are sexually active, must apply a highly effective method of birth control with a low failure rate (i.e., less than 1 percent per year), such as combined hormonal contraception (containing estrogen and progestin) combined with ovulation inhibition (oral intravaginal, or transdermal), progestin-only hormonal contraception associated with ovulation inhibition (oral, injectable, or implantable), intrauterine device (IUD), intrauterine hormone delivery system (IUS), bilateral tubal occlusion, vasectomized partner, or sexual abstinence, throughout the treatment period and for four weeks after the last dose of the study treatment. Hormonal methods other than levonorgestrel-containing devices or medroxyprogesterone injections should be supplemented with the use of a male condom. Women of nonfertile age may be included if surgically sterile or postmenopausal for at least 2 years. The investigator is responsible for determining whether the patient has adopted an appropriate method of contraception for participation in the study.
* Male subjects with female partners of childbearing age must use condoms during treatment 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 at recruitment, liver failure assessed at recruitment by clinical history and examination of ALT, AST and total bilirubin, and other contraindications to metformin 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 the investigator, would preclude participation in this study.

Primary outcomes:
measure: Value of PFS at 6 months after the start of treatment
timeFrame: Frome baseline to 6 months
Secondary outcomes:
measure: EORTC QLQ-C30 questionnaire at 6 months after the start of treatment
timeFrame: Frome baseline to 6 months
measure: MMSE questionnaire at 6 months after the start of treatment
timeFrame: Frome baseline to 6 months
measure: Safety and tolerability assessment of treatment
timeFrame: From baseline through study completion, an average of 32 months
measure: Plasma measurement of circulating metabolites
timeFrame: At study completion, an average of 32 months
measure: Plasma measurement of adiponectin
timeFrame: At study completion, an average of 32 months
measure: Proteomic analysis
timeFrame: At study completion, an average of 32 months
measure: Correlations between in vivo clinical response and effect of association measured in vitro on cell lines obtained from the same patient undergoing surgery
timeFrame: At the end of recruitment, an average of 18 months
measure: Gene expression analysis
timeFrame: At the end of recruitment, an average of 18 months
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano
Study officials:
References: