Oxidative Phosphorylation Targeting In Malignant glioma Using Metformin plus radiotherapy temozolomide

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hospital Foch

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Nervous System Diseases [C10]

Trial duration

24 Oct 2024 → ongoing

Decision date (initial)

2024-10-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-511026-31-01

EudraCT number

2021-000192-37

ClinicalTrials.gov

NCT04945148

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the progression free survival of patients with newly-diagnosed GBM IDH wild-type OXPHOS + (either with or without FGFR3-TACC3 gene fusion) treated with RT plus TMZ combined with metformin.

Secondary objectives 5

1. ✓ To evaluate the overall survival (OS) of treated patients.
2. ✓ To evaluate the overall response rate.
3. ✓ To evaluate the safety and tolerability of metformin in association with concomitant RT-TMZ
4. ✓ To investigate metabolic changes in the tumor by MR spectroscopy, namely the lactate peak variations under metformin treatment
5. ✓ To measure the penetration of metformin in the tumor at recurrence when second surgery is warranted.

Conditions and MedDRA coding

Glioblastoma grade 4

Regulatory references

Plan to share IPD

Yes

IPD plan description

IPD will be shared with Fondazione Pisana per la Scienza, located in Via Ferruccio Giovannini 13, San Giuliano Terme, 56017 (PI), Italy. Analysis will be supervised by Dr Chiara Maria MAZZANTI Italy. This laboratory is performing the screening analysis RNA seq in order to select patiens eligible for the study . The sponsor share with this laboratory the deidentified anatomopathological report and requisition form wich be sent with tumoral tissu for screening. This requisition form contain the initials of patient, the age, collection date (date of surgery), the name of surgeon.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. Provision of signed informed consent for selection and treatment phase obtained from the patient/legal representative (for patients unable to give their consent by themselves according to the article L1121-8 of “Code de la Santé Publique”) prior to performing any protocol-related procedures
2. 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
3. Newly-diagnosed histologically-confirmed supra-tentorial glioblastoma IDH wild-type (Grade IV 4 malignant glioma by World Health Organization, including gliosarcoma)
4. OXPHOS+ subtype by the central laboratory
5. No prior treatment for GBM other than surgery
6. Substantial recovery from surgical resection, no major ongoing safety issues (eg, infection requiring IV antibiotics) following surgery
7. Without corticosteroids or with stable dose of corticosteroids (ie ≤ dexamethasone 6 mg, methylprednisolone 32 mg or prednisone 40mg)
8. ECOG performance status 0-2
9. Able to receive concomitant radio-chemotherapy according to the Stupp protocol (60Gy) based on investigator judgment
10. Adequate bone marrow and normal hepatic function
11. Creatinine clearance ≥30 mL/min (between 30 and 50ml/min, patients will be prescribed no more than 1500mg of metformin)
12. Able to start RT within 7 weeks after histological diagnosis
13. Patients must have life expectancy ≥ 16 weeks
14. Patients affiliated to an appropriate health insurance system.
15. Age ≥ 18 years old
16. 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
17. 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 6 months after last dose of study drug 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.
18. 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 both investigational drug (metformin) and TMZ to undergo five half-lives. The terminal half-life of temozolomide is 1.8 hours. The terminal half-life for metformin is 6.5 hours
19. WBC ≥ 2000/μL t) Neutrophils ≥ 1500/μL
20. Platelets ≥ 100 x103/μL
21. Hemoglobin ≥ 9.0 g/dL
22. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 30 mL/min (using the Cockcroft-Gault formula)
23. AST ≤ 3.0 x ULN and ALT ≤ 3.0 x ULN and Total Bilirubin ≤ 1.5 x ULN (except patients with Gilbert Syndrome who may have a total bilirubin < 3.0 x ULN)

Exclusion criteria 23

1. Prior treatment for GBM (other than surgical resection) including Gliadel Wafer
2. Patients with hypersensitivity to dacarbazine and rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
3. Patients with severe renal insufficiency ie, CrCl < 30 mL/min (who should not receive contrast materials)
4. 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
5. Patients unable (eg, due to pacemaker or ICD device) or unwilling to have a contrast-enhanced MRI of the head
6. Any acute medical condition that may impair renal function such as dehydration, severe infection, shock
7. Any disease which may cause tissue hypoxia such as decompensated heart failure, respiratory failure, recent myocardial infarction
8. Past diabetic precoma
9. Past acute metabolic acidosis
10. Alcohol intoxication and Alcoholism
11. Persons protected by a legal regime (guardianship, trusteeship
12. 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
13. Prisoners or patients who are involuntarily incarcerated
14. Patients who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
15. Any known metastatic extracranial or leptomeningeal disease
16. IDH mutant, K27 and NTRK alterations
17. Secondary GBM (ie, progression from prior low-grade or anaplastic glioma)
18. 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 g) 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) h) Pregnant or breast-feeding women
19. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving anti-viral therapy
20. Patients with known active hepatitis (i.e., HBV or HCV)
21. Patients with a known hypersensitivity to metformin and temozolomide or any of the excipients of the products
22. 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)
23. Pregnant or breast-feeding women

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression Free Survival estimated by the RANO criteria

Secondary endpoints 6

1. ✓ Overall survival.
2. ✓ Overall response rate (ORR) estimated by the RANO criteria.
3. ✓ Safety: type, frequency, and severity (grade III and IV toxicity) of AEs and SAEs.
4. ✓ Dose interruptions, reductions, and dose intensity.
5. ✓ Time of occurrence and evaluations of laboratory values.
6. ✓ 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)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hospital Foch

Sponsor organisation

Hospital Foch

Address

40 Rue Worth

City

Suresnes

Postcode

92150

Country

France

Scientific contact point

Organisation

Hospital Foch

Contact name

Dr Anna Luisa DISTEFANO

Public contact point

Organisation

Hospital Foch

Contact name

Dr Anna Luisa DISTEFANO

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications