E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with a diagnosis of Glioblastoma |
Patients atteints d'un Glioblastome |
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E.1.1.1 | Medical condition in easily understood language |
Patients with a diagnosis of Glioblastoma |
Patients atteints d'un Glioblastome |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018337 |
E.1.2 | Term | Glioblastoma multiforme |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018336 |
E.1.2 | Term | Glioblastoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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
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- 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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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)
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- 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.
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E.4 | Principal 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
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- 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression Free Survival estimated by the RANO criteria |
Survie sans progression estimée selon les critères RANO (Response Assessement in Neuro Oncology) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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).
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- 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
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Duriing the 24 months follow-up |
Durant les 24 mois de suivi |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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LVLS |
La dernière visite du dernier patient inclus correspond à la fin de l'étude |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |