Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide (OPTIMUM)
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|ClinicalTrials.gov Identifier: NCT04945148|
Recruitment Status : Not yet recruiting
First Posted : June 30, 2021
Last Update Posted : August 3, 2022
Tailored approaches targeting crucial oncogenes and pathways have shown successful results in a number of cancer types and offer exciting perspective in neuro-oncology. IDH (Isocitrate dehydrogenase) wild-type (IDHwt) glioblastoma (GBM) (10%) present a unique and homogenous energetic metabolism which is specifically dependent on the oxidative phosphorylation (OXPHOS) rather than on the aerobic glycolysis. OXPHOS+ IDHwt GBMs overexpress mitochondrial markers and can be specifically inhibited by mitochondrial inhibitors in vitro and in vivo.
Metformin is an oral inhibitor of mitochondrial complex I and is a widely used drug in diabetic and non-diabetic patients, safe and well tolerated in association with radiotherapy and chemotherapy.
Basing on drastic effect, the investigators have observed in vivo (reduction of >50% of tumor growth) and hypothesize that metformin could be specifically efficient to treat up-front patients affected by OXPHOS+ GBM, in association with the standard first-line treatment with radiotherapy and temozolomide (RT-TMZ).
The investigators set up a dedicated molecular analysis including RNA assay and expression of OXPHOS markers for formalin-fixed paraffin-embedded tumors (FFPE), which allows to detect OXPHOS+ GBM at diagnosis.
Here a phase II, open label, non-randomized multicenter trial including five French neurooncology centers (H. Foch-Suresnes, Pitié-Salpêtrière-Paris, Saint Louis-Paris, Lyon, Marseille) and one in Italy (Istituto Besta, Milan) is proposed.
Newly diagnosed IDH wild-type GBM patients with the OXPHOS+ signature will be eligible for inclusion in this trial. The investigators expect to screen 640 patients and to include 64 patients over a period of 24 months with 24 months of follow-up.
|Condition or disease||Intervention/treatment||Phase|
|Glioblastoma, IDH-wildtype||Drug: Metformin Radiation: Radiation IMRT Drug: Temozolomide||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||640 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Metformin (1500 to 3000mg/day) in addition to Stupp protocol, starting 7 days before the start of the standard radiotherapy (RT, 60Gy/6 weeks), concomitant Temozolomide (TMZ) chemotherapy (75mg/m²/day), and adjuvant TMZ (150-200 mg/m2/ 5 days) + metformin will follow onwards until the 12th cycle of TMZ|
|Masking:||None (Open Label)|
|Official Title:||Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide|
|Estimated Study Start Date :||October 2022|
|Estimated Primary Completion Date :||October 2026|
|Estimated Study Completion Date :||October 2026|
Patients who have been selected with an OXPHOS+ status, will start standard radiotherapy (RT, 60Gy/6 weeks), concomitant TMZ chemotherapy (75mg/m²/day), and metformin by 7 weeks after surgery and adjuvant TMZ + metformin will follow onwards until the 12th cycle of TMZ. Patients still in remission after this time-point will continue metformin alone until progression.
Metformin 2000 to 3000mg/day daily will be started by 6 weeks after histological diagnosis and 7 days before the start of RT-TMZ and will continue until progression.
Radiation: Radiation IMRT
2 Gy x 5 days for 6 weeks to be started 7 days after first administration of Metformin and by 7 weeks after histological diagnosis
Other Name: Radiation
75 mg/m² daily from first to last day of radiation (IMRT) and then 150 to 200 mg/m² x 5 days every 28 days cycle for 12 cycles
- Assessement of Progression Free Survival (PFS) 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 [ Time Frame: During the 24 months of follow-up ]Progression free survival (PFS) estimated by the RANO (Response Assesment in Neuro Oncology) criteria
- Assessement of the Overall survival (OS) of treated patients [ Time Frame: During the 24 months of follow-up ]Overall survival (OS)
- Assessement of the Overall Response rate (ORR) [ Time Frame: During the 24 months of follow-up ]Overall response rate (ORR) estimated by the RANO criteria
- Assessement of the the safety of metformin in association with concomitant RT-TMZ [ Time Frame: During the 24 months of follow-up ]Type, frequency, and severity (grade III and IV toxicity) of Adverse Events (AEs) and Serious Adverse Events (SAEs)
- Assessement of the the tolerability of metformin in association with concomitant RT-TMZ [ Time Frame: During the 24 months of follow-up ]Dose interruptions, reductions and dose intensity.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04945148
|Contact: Anna Luisa DI STEFANO, MD||01 46 25 37 22 ext 00 email@example.com|
|Contact: Elisabeth HULIER-AMMAR, PhD||01 46 25 11 75 ext 00 firstname.lastname@example.org|
|Suresnes, Hauts De Seine, France, 92150|
|Contact: Anna Luisa DI STEFANO, MD 01 46 25 37 22 ext 0033 email@example.com|
|Hôpital Neurologique Pierre Wertheimer|
|Bron, Lyon, France, 69500|
|Contact: François DUCRAY, PUPH firstname.lastname@example.org|
|Marseille, France, 13354|
|Contact: Olivier CHINOT, PUPH email@example.com|
|Saint Louis Hospital|
|Paris, France, 75010|
|Contact: Antoine CARPENTIER, PUPH firstname.lastname@example.org|
|Pitié Salpêtrière Hospital|
|Paris, France, 75013|
|Contact: Marc SANSON, PUPH email@example.com|
|Istituto Nazionale Carlo Besta|
|Milano, Italy, 20131|
|Contact: Marica EOLI, MD firstname.lastname@example.org|
|Principal Investigator:||Anna Luisa DI STEFANO, MD||Foch Hospital|