Glioblastoma, IDH-wildtypePhase 2OPTIMUMNCT04945148
Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide
A Phase 2 study testing Metformin, Radiation IMRT and Temozolomide in people with Glioblastoma, IDH-wildtype, run by Hopital Foch at 7 sites in 2 countries.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Glioblastoma, IDH-wildtype
- What is being tested?
- Metformin, Radiation IMRT and Temozolomide
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 640 participants
- Where
- 7 sitesin 2 countries
- Study dates
- 10 May 2024to May 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Provision of signed informed consent for selection and treatment phase obtained from the patient/legal representative prior to performing any protocol-related procedures,
- Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits, and examinations including follow-up,
- Newly-diagnosed histologically-confirmed supra-tentorial IDHwt glioblastoma (Grade 4 malignant glioma by World Health Organization, including gliosarcoma),
- 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 I.V. antibiotics) following surgery,
Show all 26Show fewer
- Without corticosteroids or with stable dose of corticosteroids (ie ≤ dexamethasone 6 mg, methylprednisolone 30 mg or prednisone 38 mg),
- ECOG (Eastern Cooperative Oncology Group) 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 50 ml/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,
- Age ≥ 18 years old,
- 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,
- Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception from the signing of the informed consent and continue throughout period of taking study treatment and for 30 days after last dose of study drug (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half-lives (both TMZ and metformin). The terminal half-life of temozolomide is 1.8 hours. The terminal half-life for metformin is 6.5 hours.
- Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception throughout the period of taking study treatment and for 6 months plus the time required for the investigational drug to undergo five half-lives (both TMZ and metformin). The terminal half-life of temozolomide is 1.8 hours. The terminal half-life for metformin is 6.5 hours.
- White blood cells (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) Female CrCl = (140-age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140-age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL
- Aspartate AminoTransferase (AST) ≤ 3.0 x ULN,
- Alanine Aminotransferase (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).
Who cannot join
- 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,
Show all 22Show fewer
- 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., Hepatitis B Virus (HBV) or Hepatitis C Virus (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 Implantable Cardioverter Defibrillator (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
- Past Diabetic precoma
- Past 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.
Trial locations and contacts
7 sites in 2 countries. Contact the study team or a site near you to ask about taking part.
7 sites in 2 countries
France5 sites, 5 recruiting
- Recruiting
Hôpital Neurologique Pierre Wertheimer
Bron, Lyon, 69500
François DUCRAY, PUPH, francois.ducray@chu-lyon.fr
- Recruiting
Timone Hospital
Marseille, Marseille, 13354
Olivier CHINOT, PUPH, olivier.chinot@ap-hm.fr
- Recruiting
Saint Louis Hospital
Paris, Paris, 75010
Stefania Cuzzubbo, PUPH, 0171207466 ext. 331, stefania.cuzzubbo@aphp.fr@aphp.fr
- Recruiting
Pitié Salpêtrière Hospital
Paris, PARIS, 75013
Marc SANSON, PUPH, marc.sanson@aphp.fr
- Recruiting
Foch Hospital
Suresnes, Hauts de Seine, 92150
Nadia YOUNAN, MD, 01 46 25 31 41 ext. 0033, n.younan@hopital-foch.com
Italy2 sites, 2 recruiting
- Not yet recruiting
Spidali Riuniti Di Livorno
Livorno, Toscana Nord Ouest, 57100
Anna Luisa DI STEFANO, annaluisa.distefano@uslnordovest.toscana.it
- Not yet recruiting
Istituto Nazionale Carlo Besta
Milan, Milano, 20131
Marica EOLI, MD, marica.eoli@istituto-besta.it
About this study
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.
Read more
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.
- Conditions
- Glioblastoma, IDH-wildtype
- Being tested
- Metformin, Radiation IMRT, Temozolomide
- Keywords
- Glioblastoma, FGFR3-TACC3, Metformin, Radio-chemotherapy, OXPHOS+
- Medical subject headings
- Glioblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
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 IMRTRadiation
Also called Radiation
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
TemozolomideDrug
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
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | 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. Receives: Drug: Metformin; Radiation: Radiation IMRT; Drug: Temozolomide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Progression free survival (PFS) estimated by the RANO (Response Assesment in Neuro Oncology) criteria
Measured: During the 24 months of follow-up
Secondary outcomes (4)
Assessement of the Overall survival (OS) of treated patients
Overall survival (OS)
Measured: During the 24 months of follow-up
Assessement of the Overall Response rate (ORR)
Overall response rate (ORR) estimated by the RANO criteria
Measured: During the 24 months of follow-up
Assessement of the the safety of metformin in association with concomitant RT-TMZ
Type, frequency, and severity (grade III and IV toxicity) of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Measured: During the 24 months of follow-up
Assessement of the the tolerability of metformin in association with concomitant RT-TMZ
Dose interruptions, reductions and dose intensity.
Measured: During the 24 months of follow-up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jun 2021
- Study start10 May 2024
- Primary completionMay 2028 (estimated)
- Study completionMay 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Glioblastoma, IDH-wildtypeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- 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)
- Enrolment
- 640 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hopital Foch
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute, France
- Responsible party
- Sponsor
- Investigators
- Anna Luisa DI STEFANO, MD, Principal investigator, Foch Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04945148
- Sponsor's protocol ID
- 2019_0007
- Acronym
- OPTIMUM
- Status last verified
- Nov 2025
- First submitted
- 25 Jun 2021
- Last updated
- 21 Nov 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oxidative Phosphorylation Targeting In Malignant Glioma Using Metformin Plus Radiotherapy Temozolomide
- ClinicalTrials.gov ID
- NCT04945148
- Acronym / sponsor ID
- OPTIMUM / 2019_0007
- Conditions
- Glioblastoma, IDH-wildtype
- Keywords
- Glioblastoma, FGFR3-TACC3, Metformin, Radio-chemotherapy, OXPHOS+
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 640 participants (estimated)
- Lead sponsor
- Hopital FochUniversity, hospital or other
- Collaborators
- National Cancer Institute, France
- Study start
- 10 May 2024 (actual)
- Primary completion
- May 2028 (estimated)
- Study completion
- May 2028 (estimated)
- First posted
- 30 Jun 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- 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
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: Metformin, Radiation: Radiation IMRT, Drug: TemozolomidePatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (26 listed)
- Provision of signed informed consent for selection and treatment phase obtained from the patient/legal representative prior to performing any protocol-related procedures,
- Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits, and examinations including follow-up,
- Newly-diagnosed histologically-confirmed supra-tentorial IDHwt glioblastoma (Grade 4 malignant glioma by World Health Organization, including gliosarcoma),
- OXPHOS+ subtype by the central laboratory
- No prior treatment for GBM other than surgery,
Key exclusion criteria (22 listed)
- 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),
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminMetformin 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. | Drug | Metformin |
| Radiation IMRTAlso: Radiation2 Gy x 5 days for 6 weeks to be started 7 days after first administration of Metformin and by 7 weeks after histological diagnosis | Radiation | Metformin |
| Temozolomide75 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 | Drug | Metformin |
Primary outcome
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
4 secondary outcomes
Assessement of the Overall survival (OS) of treated patients
Time frame: During the 24 months of follow-up
Assessement of the Overall Response rate (ORR)
Time frame: During the 24 months of follow-up
Assessement of the the safety of metformin in association with concomitant RT-TMZ
Time frame: During the 24 months of follow-up
Assessement of the the tolerability of metformin in association with concomitant RT-TMZ
Time frame: During the 24 months of follow-up
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Nov 2025.
- Individual participant dataSharing planned: No
Related trials for Glioblastoma, IDH-wildtype
RecruitingPhase 1/2
Testing the Addition of an Anti-cancer Drug, Selinexor, to the Usual Chemotherapy Treatment (Temozolomide) for Brain Tumors That Have Returned After Previous Treatment
Recurrent Glioblastoma, IDH-Wildtype, Recurrent MGMT-Methylated Glioblastoma
RecruitingPhase 1
Anti-GD2 ADC M3554 in Advanced Solid Tumors
Advanced Solid Tumor
RecruitingPhase 2/3
A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma
Glioblastoma
Not yet recruitingEarly Phase 1
Biomarker-guided RAdiation-deferring Treatment in Younger GBM Patients - Pilot Study
IDH Wildtype Glioblastoma, Glioblastoma (GBM)
RecruitingPhase 2
GI-102 Alone or With Pembrolizumab Before Surgery for Treatment of Recurrent or Progressive IDH Wildtype Glioblastoma and IDH Mutated Grade 4 Astrocytoma
Glioblastoma, IDH-Wildtype, Progressive Astrocytoma, IDH-Mutant, Grade 4
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Anna Luisa DI STEFANO, MD principal investigator
Foch Hospital
7 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Metformin, Radiation IMRT and Temozolomide in people with Glioblastoma, IDH-wildtype, run by Hopital Foch at 7 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 26 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 21 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in France, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Anna Luisa DI STEFANO, MD (01 46 25 37 22 ext. 00 33, al.di-stefano@hopital-foch.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Nov 2025.