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    Summary
    EudraCT Number:2022-003595-16
    Sponsor's Protocol Code Number:GBM-MET
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2023-01-31
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2022-003595-16
    A.3Full title of the trial
    Phase 2, open-label, single-arm study on the use of metformin as adjunctive therapy in high-grade glioma
    Studio di fase 2, in aperto, a singolo braccio sull’uso della metformina come terapia aggiuntiva nel glioma di alto grado
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial on the use of metformin in addition to standard therapy in patients with high-grade glioma
    Studio clinico sull'uso della metformina in aggiunta alla terapia standard in pazienti affetti da glioma di alto grado
    A.3.2Name or abbreviated title of the trial where available
    GBM-MET
    GBM-MET
    A.4.1Sponsor's protocol code numberGBM-MET
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUNIVERSITÀ DEGLI STUDI MILANO BICOCCA
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAIRC
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversità degli Studi di Milano-Bicocca
    B.5.2Functional name of contact pointBicocca Clinical Research Office
    B.5.3 Address:
    B.5.3.1Street Addressvia Pergolesi, 33
    B.5.3.2Town/ cityMonza
    B.5.3.3Post code20900
    B.5.3.4CountryItaly
    B.5.4Telephone number0264488155
    B.5.6E-mailbicro@unimib.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namemetformina
    D.3.2Product code metformina
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMETFORMINA CLORIDRATO
    D.3.9.2Current sponsor codemetformina
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    IDH-wildtype glioblastoma
    glioblastoma IDH-wildtype (GBM)
    E.1.1.1Medical condition in easily understood language
    High-grade glioblastoma
    Glioblastoma di alto grado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10018336
    E.1.2Term Glioblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Determine efficacy at the recommended dose of metformin in patients with glioblastoma. Efficacy will be assessed by PFS at 6 months after initiation of treatment. Radiographic response will be assessed by RANO (Response Assessment in Neurooncology) criteria compared with the patient's condition at baseline (MRI performed post-surgery).
    Determinare l'efficacia alla dose raccomandata di metformina nei pazienti con glioblastoma. L’efficacia sarà valutata tramite la PFS a 6 mesi dall’inizio del trattamento. La risposta radiografica sarà valutata in base ai criteri RANO (Response Assessment in Neurooncology) comparati con la condizione del paziente al baseline (MRI effettuata post-chirurgia).
    E.2.2Secondary objectives of the trial
    1) Assessment of change in health-related quality of life (EORTC QLQ-C30 and MMSE) at 6 months after the start of treatment.
    2) Evaluation safety and tolerability of treatment measured as frequency and severity of adverse events throughout the study. The data obtained will be compared with historical data.
    3) Search for clinical and plasma prognostic biomarkers.
    4) Exploration of possible correlations between in vivo clinical response and effect of association measured in vitro on cell lines obtained from the same patient undergoing surgery.
    1) Valutazione della variazione del livello di qualità della vita correlata alla salute (EORTC QLQ-C30 e MMSE) a 6 mesi dall’inizio del trattamento.
    2) Valutazione sicurezza e tollerabilità del trattamento misurata come frequenza e gravità di eventi avversi nel corso dell’intero studio. I dati ottenuti verranno confrontati con dati storici.
    3) Ricerca di biomarcatori prognostici clinici e plasmatici.
    4) Esplorazione di eventuali correlazioni tra la risposta clinica in vivo ed effetto dell’associazione misurata in vitro su linee cellulari ottenute dallo stesso paziente in fase chirurgica.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients with newly diagnosed histologically confirmed GBM (WHO grade IV, IDH wild type) undergoing surgical resection;
    - Hypomethylation or hypermethylation of MGMT evaluated post-surgery;
    - Adult patients (=18 years), both sexes;
    - Patients undergoing Stupp protocol including patients aged >70 years performing hypofractionated protocol and three weeks of chemotherapy;
    - Karnofsky Performance Status (KPS) > 60 assessed post-surgery;
    - Life expectancy at least 6 months defined by tumor lesion size and location;
    - Freely given written informed consent prior to any study-related activity. Patients must be able to communicate with the investigator and comply with study procedures;
    - Women of childbearing age must test negative for pregnancy at enrollment and, if they have sex, must agree to use specific contraceptive methods. Female subjects of childbearing age, i.e., fertile, after menarche and until post-menopause unless 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.
    • Pazienti affetti da nuova diagnosi di GBM istologicamente confermata (WHO grado IV, IDH wild type) sottoposti a resezione chirurgica;
    • Ipometilazione o ipermetilazione di MGMT valutata post-chirurgia;
    • Pazienti adulti (= 18 anni), entrambi i sessi;
    • Pazienti sottoposti a protocollo Stupp inclusi i pazienti con età > 70 anni che eseguono il protocollo ipofrazionato e tre settimane di chemioterapia;
    • Karnofsky Performance Status (KPS)> 60 valutato post chirurgia;
    • Aspettativa di vita almeno 6 mesi definita in base alla dimensione e posizione della lesione tumorale;
    • Consenso informato scritto e liberamente concesso prima di qualsiasi attività correlata allo studio. I pazienti devono essere in grado di comunicare con lo sperimentatore e rispettare le procedure dello studio;
    • Le donne in età fertile devono risultare negative al test di gravidanza all’arruolamento e, se hanno rapporti sessuali, devono accettare di utilizzare metodi contraccettivi specifici. I soggetti di sesso femminile in età fertile, cioè fertili, dopo il menarca e fino alla post-menopausa a meno che non siano permanentemente sterili, che sono sessualmente attivi, devono applicare un metodo di controllo delle nascite altamente efficace con un basso tasso di fallimento (cioè meno dell'1% all'anno), come ad esempio la contraccezione ormonale combinata (contenente estrogeni e progestinici) associata all'inibizione dell'ovulazione (orale, intravaginale o transdermica), contraccezione ormonale a base di solo progestinico associata all'inibizione dell'ovulazione (orale, iniettabile o impiantabile), dispositivo intrauterino (IUD), sistema di rilascio ormonale intrauterino (IUS), occlusione tubarica bilaterale, partner vasectomizzato o astinenza sessuale, per tutto il periodo di trattamento e per quattro settimane dopo l'ultima dose del trattamento in studio. I metodi ormonali diversi dai dispositivi contenenti levonorgestrel o dalle iniezioni di medrossiprogesterone devono essere integrati con l'uso di un preservativo maschile. Le donne in età non fertile possono essere incluse se chirurgicamente sterili o in post-menopausa da almeno 2 anni. Lo sperimentatore è responsabile di determinare se il paziente ha adottato un adeguato metodo di contraccezione per la partecipazione allo studio.
    • I soggetti di sesso maschile con partner femminili in età fertile devono utilizzare il preservativo durante il trattamento e fino al termine della relativa esposizione sistemica.
    E.4Principal 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;
    - The patient has serious pre-existing medical conditions that, in the opinion of the investigator, would preclude participation in this study.
    • GBM multicentrici;
    • Pazienti con diagnosi di diabete o patologie legate al diabete;
    • Altri tumori maligni attivi;
    • Ipersensibilità, intolleranza a metformina o eccipienti;
    • Ridotta funzionalità renale con clearance creatinina < 60 mL/min valutata al reclutamento, insufficienza epatica valutata al reclutamento mediante anamnesi clinica ed esame di ALT, AST e bilirubina totale e altre controindicazioni all’uso della metformina;
    • Assunzione di metformina, insulina o altri biguanidi, indipendentemente dal motivo;
    • Gravidanza o allattamento;
    • Il paziente ha gravi condizioni mediche preesistenti che, a giudizio dello sperimentatore, precluderebbero la partecipazione a questo studio.
    E.5 End points
    E.5.1Primary end point(s)
    PFS assessed at V3 (at approximately 6 months after treatment initiation). Progression is defined as recurrence from documentable disease on MRI by assessment with RANO (Response Assessment in Neurooncology) criteria (MRI T1w-Gd; T2 Flair).
    PFS valutata a V3 (a circa 6 mesi dall’inizio del trattamento). La progressione è definita come ripresa da malattia documentabile alla risonanza tramite valutazione con i criteri RANO (Response Assessment in Neurooncology) (MRI T1w-Gd; T2 Flair).
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months after treatment initiation
    6 mesi dall’inizio del trattamento
    E.5.2Secondary end point(s)
    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 (blood count, liver and kidney toxicity, blood glucose) assessed during the study.; Health-related quality of life measured by EORTC QLQ-C30 and MMSE questionnaires assessed at V0 and V3. The data obtained will be compared with population data.; - In vitro response of cells taken from patients' tissue samples during surgery to treatment with TMZ or TMZ plus MET or vehicle measured as cell growth inhibition and correlation with clinical response (PFS) of the same patient.
    - Transcriptomic analysis to identify the molecular phenotype of cells taken from patients' tissue samples during surgery and comparison between clinical response and molecular phenotype.
    Evaluation of these endpoints will be performed at the end of recruitment.; Plasma measurement of circulating metabolites, adiponectin and proteomic analysis as potential prognostic and response markers. Overall assessment of this endpoint will be performed at the end of the study.
    La sicurezza verrà valutata per tutta la durata dello studio come tipo, frequenza e severità di eventi grado III e IV. La tollerabilità sarà valutata come numero di interruzioni o riduzione del dosaggio e mediante la valutazione di parametri clinici ed ematochimici (emocromo, tossicità epatica e renale, glicemia) valutati durante lo studio.; Qualità della vita correlata alla salute misurata tramite i questionari EORTC QLQ-C30 e MMSE valutati a V0 e V3. I dati ottenuti verranno confrontati con i dati di popolazione.; - Risposta in vitro delle cellule prelevate dai campioni di tessuto dei pazienti durante la chirurgia a trattamento con TMZ o TMZ più MET o veicolo misurata come inibizione di crescita cellulare e correlazione con la risposta clinica (PFS) dello stesso paziente.
    - Analisi trascrittomica per identificare il fenotipo molecolare delle cellule prelevate dai campioni di tessuto dei pazienti durante la chirurgia e confronto tra risposta clinica e fenotipo molecolare.
    La valutazione di questi endpoint verrà eseguita al termine del reclutamento.; Misurazione plasmatica di metaboliti circolanti, adiponectina ed analisi proteomica come potenziali marcatori prognostici e di risposta. La valutazione complessiva di questo endpoint verrà eseguita alla fine dello studio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The entire duration of the study, about 58 weeks.; V3 (22 weeks from the start of treatment); End of recruitment period; End of the study
    L'intera durata dello studio, circa 58 settimane.; V3 (22 settimane dall'inizio del trattamento); Fine del periodo di reclutamento; Fine dello studio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 25
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of the study, patients will continue to be monitored according to regular clinical pratice
    I pazienti al termine dello studio continueranno il monitoraggio e gestione regolare secondo pratica clinica
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2023-04-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-05-23
    P. End of Trial
    P.End of Trial StatusOngoing
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