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    Summary
    EudraCT Number:2021-000192-37
    Sponsor's Protocol Code Number:2019_0007
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-05-26
    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 ConcernedFrance - ANSM
    A.2EudraCT number2021-000192-37
    A.3Full title of the trial
    Oxidative Phosphorylation Targeting In Malignant glioma Using Metformin plus radiotherapy temozolomide
    La metformine en association avec radiothérapie-témozolomide comme thérapie ciblée métabolique pour le sous-groupe de patients atteints d’un glioblastome dépendant de la phosphorylation oxydative
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Oxidative Phosphorylation Targeting In Malignant glioma Using Metformin plus radiotherapy temozolomide
    La metformine en association avec radiothérapie-témozolomide comme thérapie ciblée métabolique pour le sous-groupe de patients atteints d’un glioblastome dépendant de la phosphorylation oxydative
    A.3.2Name or abbreviated title of the trial where available
    OPTIMUM
    OPTIMUM
    A.4.1Sponsor's protocol code number2019_0007
    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 SponsorHôpital Foch
    B.1.3.4CountryFrance
    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 supportDelegation of Clinical Research and Innovation (DRCI), Hôpital Foch
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHôpital Foch
    B.5.2Functional name of contact pointDRCI
    B.5.3 Address:
    B.5.3.1Street Address40 Rue Worth
    B.5.3.2Town/ citySuresnes
    B.5.3.3Post code92150
    B.5.3.4CountryFrance
    B.5.4Telephone number+33146 25 27 05
    B.5.5Fax number+33146 25 27 66
    B.5.6E-maildrci-promotion@hopital-foch.com
    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.2.1.1.1Trade name METFORMINE
    D.2.1.1.2Name of the Marketing Authorisation holderARROW GENERIQUES
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameMetformine
    D.3.4Pharmaceutical form 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 INNMETFORMIN HYDROCHLORIDE
    D.3.9.3Other descriptive nameMETFORMIN
    D.3.9.4EV Substance CodeSUB03200MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number390
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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
    Patients with a diagnosis of Glioblastoma
    Patients atteints d'un Glioblastome
    E.1.1.1Medical condition in easily understood language
    Patients with a diagnosis of Glioblastoma
    Patients atteints d'un Glioblastome
    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 10018337
    E.1.2Term Glioblastoma multiforme
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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
    To assess the progression free survival of patients with newly-diagnosed IDH wild-type OXPHOS + GBM (either with or without FGFR3-TACC3 gene fusion) treated with RT plus TMZ combined with metformin
    Evaluer la survie sans progression des patients atteints de Glioblastome IDH et ATRX de type sauvage, OXPHOS+, traités par radiothérapie plus témozolomide combinés à la metformine.
    E.2.2Secondary objectives of the trial
    To evaluate the overall survival (OS) of treated patients.
    To evaluate the overall response rate.
    To evaluate the safety and tolerability of metformin in association with concomitant RT-TMZ
    - Evaluer la survie globale des patients traités
    - Evaluer le taux de réponse globale
    - Évaluer l'innocuité et la tolérance de la metformine en association avec RT-TMZ
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age ≥ 18 years old
    - Newly-diagnosed histologically-confirmed supra-tentorial glioblastoma (Grade IV malignant glioma by World Health Organization, including gliosarcoma), IDH wild-type glioblastoma
    - OXPHOS+ subtype by the central laboratory
    - No prior treatment for GBM other than surgery
    - Substantial recovery from surgical resection, no major ongoing safety issues (eg, infection requiring IV antibiotics) following surgery
    - Without corticosteroids or with stable dose of corticosteroids (ie ≤ dexamethasone 6 mg, methylprednisolone 30 mg or prednisone 38 mg)
    - ECOG performance status 0-2
    - Able to receive concomitant radio-chemotherapy according to the Stupp protocol (60Gy) based on investigator judgment
    - Adequate bone marrow and normal hepatic function
    - Creatinine clearance ≥30 mL/min (between 30 and 50ml/min, patients will be prescribed no more than 1500mg of metformin)
    - Able to start RT within 7 weeks after histological diagnosis
    - Patients must have life expectancy ≥ 16 weeks
    -Patients affiliated to an appropriate health insurance system
    - Provision of signed informed consent for selection and treatment phase obtained from the patient/legal representative prior to performing any protocol-related procedures
    - 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
    - WBC ≥ 2000/μL
    - Neutrophils ≥ 1500/μL
    - Platelets ≥ 100 x103/μL
    - Hemoglobin ≥ 9.0 g/dL
    - Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 30 mL/min (using the Cockcroft-Gault formula).
    - AST ≤ 3.0 x ULN
    - ALT ≤ 3.0 x ULN
    - Total Bilirubin ≤ 1.5 x ULN (except patients with Gilbert Syndrome who may have a total bilirubin < 3.0 x ULN)
    - Age ≥ 18 ans,
    - Glioblastome supra-tentoriel nouvellement diagnostiqué et confirmé histologiquement,
    - Sous-type transcriptomique OXPHOS + selon le test RNASeq,
    - Aucun traitement antérieur pour le glioblastome autre que la chirurgie,
    - Sans corticostéroïdes ou avec une dose stable de corticostéroïdes (c'est-à-dire ≤ dexaméthasone 6 mg, méthylprednisolone 30 mg ou prednisone 38 mg),
    - Statut de performance ECOG 0-2,
    - Clairance de la créatinine ≥ 30 ml / min (entre 30 et 50 ml / min, les patients ne se verront pas prescrire plus de 1500 mg de metformine),
    - GB ≥ 2000 / μL,
    - Neutrophiles ≥ 1500 / μL,
    - Plaquettes ≥ 100 x103 / μL,
    - Hémoglobine ≥ 9,0 g / dL,
    - Créatinine sérique ≤ 1,5 x ULN,
    - ASAT ≤ 3.0 x ULN,
    - ALAT ≤ 3.0 x ULN,
    - Bilirubine totale ≤ 1.5 x ULN,
    - Pour les femmes en âge de procréer, test de grossesse sérique négatif réalisé dans les 7 jours précédant le début du traitement,
    - Les femmes en âge de procréer doivent accepter d’être sous contraception dès la signature du consentement et jusqu’à 30 jours après la dernière prise du médicament dans le cadre de l’étude (durée du cycle ovulatoire).
    - Les hommes sexuellement actifs doivent accepter de suivre une méthode de contraception pendant toute la durée du traitement de l’étude et jusqu’à 90 jours après la dernière prise du médicament dans le cadre de l’étude (durée du renouvellement du sperme),
    - Ayant signé un consentement libre et éclairé pour la phase de sélection et la phase de traitement,
    - Affilié à un régime d’assurance maladie.
    E.4Principal exclusion criteria
    - Prior treatment for GBM (other than surgical resection) including Gliadel Wafer
    - 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
    - Any known metastatic extracranial or leptomeningeal disease
    - IDH mutant
    - Secondary GBM (ie, progression from prior low-grade or anaplastic glioma)
    - 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
    - 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)
    - Pregnant or breast-feeding women
    - Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving anti-viral therapy
    - Patients with known active hepatitis (i.e., HBV or HCV)
    - Patients with a known hypersensitivity to metformin and temozolomide or any of the excipients of the products
    - Patients with severe renal insufficiency ie, CrCl < 30 mL/min (who should not receive contrast materials)
    - 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
    - Patients unable (eg, due to pacemaker or ICD device) or unwilling to have a contrast-enhanced MRI of the head
    - Any acute medical condition that may impair renal function such as dehydration, severe infection, shock
    - Any disease which may cause tissue hypoxia such as decompensated heart failure, respiratory failure, recent myocardial infarction
    - Diabetic precoma
    - Acute metabolic acidosis
    - Alcohol intoxication and Alcoholism
    - Persons protected by a legal regime (guardianship, trusteeship).
    - Prisoners or patients who are involuntarily incarcerated
    -Patients who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
    - Patients atteints d'un deuxième cancer primaire, sauf: cancer de la peau non mélanique correctement traité, cancer in situ du col de l'utérus traité de manière curative ou autres tumeurs solides traitées de manière curative sans signe de maladie pendant ≥ 5 ans,
    - Toute maladie métastatique extracrânienne ou leptoméningée connue,
    - Mutant IDH,
    - GBM secondaire (c.-à-d. Progression d'un gliome de bas grade ou anaplasique antérieur),
    - Patients incapables d'avaler les médicaments administrés par voie orale et patients présentant des troubles gastro-intestinaux susceptibles d'interférer avec l'absorption du médicament à l'étude (maladie inflammatoire de l'intestin, résection intestinale majeure),
    - Femmes enceintes ou allaitantes,
    - Patients immunodéprimés,
    - Patients atteints d'hépatite active connue (Hépatite B ou C),
    - Patients présentant une hypersensibilité connue à la metformine et au témozolomide ou à l'un des excipients des produits,
    - Acidose métabolique aiguë,
    - Intoxication alcoolique et alcoolisme chronique,
    - Patients incapables (En raison d'un stimulateur cardiaque ou d'un dispositif DAI) ou refusant de subir une IRM cérébrale,
    - Patient privé de liberté ou sous tutelle,
    - Antécédents ou preuves à l'examen physique / neurologique d'une autre affection du système nerveux central (Convulsions, abcès) sans rapport avec le cancer, à moins qu'elles ne soient adéquatement contrôlées par des médicaments ou considérées comme ne pouvant pas interférer avec le traitement du protocole.
    E.5 End points
    E.5.1Primary end point(s)
    Progression Free Survival estimated by the RANO criteria
    Survie sans progression estimée selon les critères RANO (Response Assessement in Neuro Oncology)
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 12 month
    à 12 mois
    E.5.2Secondary end point(s)
    - Overall survival.
    - Overall response rate (ORR) estimated by the RANO criteria.
    - Safety: type, frequency, and severity (grade III and IV toxicity) of AEs and SAEs.
    - Dose interruptions, reductions and dose intensity.
    - Time of occurrence and evaluations of laboratory values.
    - Several safety aspects will be recorded such as haematological toxicity (and related risks of infection and bleeding), hypersensitivity requiring treatment interruption, digestive effects (nausea, vomiting, constipation).
    - Survie globale
    - Taux de réponse globale (ORR) estimée selon les critères RANO
    - Pharmacovigilance : type, fréquence et gravité des effets indésirables et des effets indésirables graves; (toxicités de niveaux III et IV)
    - Interruptions et réductions de nombre et d’intensité de dose
    - Evolution des paramètres biologiques
    E.5.2.1Timepoint(s) of evaluation of this end point
    Duriing the 24 months follow-up
    Durant les 24 mois de suivi
    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 No
    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.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA1
    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 No
    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
    La dernière visite du dernier patient inclus correspond à la fin de l'étude
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 32
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 32
    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 Yes
    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 state59
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 5
    F.4.2.2In the whole clinical trial 64
    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)
    None
    Aucun
    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 Decision2021-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-07-06
    P. End of Trial
    P.End of Trial StatusOngoing
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