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

Metformin Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05929495
• Other study ID #: GBM MET
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: December 1, 2023
• Est. completion date: January 1, 2026

Study information

• Verified date: November 2023
• Source: University of Milano Bicocca
• Contact: Manuela Caroli, Dott.ssa
• Phone: 0255035502
• Email: manuela.caroli[@]policlinico.mi.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 25
• Est. completion date: January 1, 2026
• Est. primary completion date: January 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Glioblastoma
• Glioblastoma, IDH-wildtype
• Glioma
• Malignancies
• Metformin

Intervention

Drug:
• Metformin
The investigator will identify potential participants and confirm the diagnosis of GBM. Subjects will be screened within 6 weeks before starting treatment. Treatment will involve: Administration of the standard or partial Stupp protocol (Radiotherapy + Temozolomide) in combination with Metformin for 6 weeks, Treatment with only Metformin for 4 weeks; Resumption of adjuvant TMZ + Metformin treatment continuously until the end of the enrollment period.

Locations

Country	Name	City	State
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano	Milan

Sponsors (1)

Lead Sponsor	Collaborator
University of Milano Bicocca

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Value of PFS at 6 months after the start of treatment	It allow us to determine the efficacy at the recommended dose (RD) of metformin in patients with GBM	Frome baseline to 6 months
Secondary	EORTC QLQ-C30 questionnaire at 6 months after the start of treatment	The Quality of Life of Cancer Patients questionnaire allow us to evaluate the change in the level of health-related quality of life.; It consists of several questions that the patient must answer by choosing a value from 1 (minimum) to 4/7 (maximum), depending on the question.	Frome baseline to 6 months
Secondary	MMSE questionnaire at 6 months after the start of treatment	The Mini Mental State Evaluation questionnaire allow us to evaluate the change in the level of health-related quality of life.; It consists of several questions for the patient to answer, but there are no minimum or maximum values for the patient to choose from.	Frome baseline to 6 months
Secondary	Safety and tolerability assessment of treatment	Safety will be assessed throughout the study as type, frequency and severity of grade III and IV events.; Tolerability will be assessed as number of discontinuations or dose reduction and by evaluation of clinical and hematochemical parameters	From baseline through study completion, an average of 32 months
Secondary	Plasma measurement of circulating metabolites	Peri-operative plasma will be taken from each patient for hematochemical analysis, in order to research of prognostic biomarkers.	At study completion, an average of 32 months
Secondary	Plasma measurement of adiponectin	Peri-operative plasma will be taken from each patient for hematochemical analysis, in order to research of prognostic biomarkers.	At study completion, an average of 32 months
Secondary	Proteomic analysis	Peri-operative plasma will be taken from each patient for proteomic analysis, in order to research of prognostic biomarkers.	At study completion, an average of 32 months
Secondary	Correlations between in vivo clinical response and effect of association measured in vitro on cell lines obtained from the same patient undergoing surgery	In vitro cell response measured as cell growth inhibition and correlation with clinical response (PFS) of the same patient.	At the end of recruitment, an average of 18 months
Secondary	Gene expression analysis	Identifying the molecular phenotype of cells taken from patients' tissue samples during surgery and comparing clinical response and molecular phenotype by transcriptomic analysis	At the end of recruitment, an average of 18 months