Phase-1 Study of Folinic Acid to Modulate MGMT Gene in Glioblastoma

Glioblastoma Clinical Trial

— FOLAGLI  

Official title:

Phase I Study of Escalated Pharmacologic Dose, of Oral Folinic Acid in Combination With Temozolomide, According to Stupp R. Regimen, in Patients With Operated Grade-IV Astocytoma and a Non-methylated Gene Status of MGMT.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01700569
• Other study ID #: ICO 2012-02
• Secondary ID: 2012-000774-31
• Status: Terminated
• Phase: Phase 1
• Start date: January 2013
• Est. completion date: April 16, 2021

Study information

• Verified date: May 2021
• Source: Institut Cancerologie de l'Ouest
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

O6-méthylguanine méthyltransférase (MGMT) is the main repair gene after DNA lesion induced by Temozolomide in combination with radiation therapy of Glioblastoma (GBM) in Stupp.R et al published regimen. In preclinical models, it has been demonstrated that MGMT methylation (which is silencing the DNA repair process) is achievable by folic acid. About half of the patients with operated GBM have an un-methylated MGMT gene status and therefore a poorer prognosis. A phase-1 dose escalation study is proposed with pharmacologic doses of folinic acid in combination with temozolomide and radiotherapy of operated GBM.

Description:

Glioblastoma treated by Stupp regimen (Temozolomide + radiation therapy) have a different outcome depending on the methylation status of MGMT gene: when the gene is unmethylated, the repair process is active and the prognostic poor. In pre-clinical models, it has been demonstrated that Folic acid could re-methylate the MGMT gene and therefore the repair process to radiation and temozolomide could be limited, allowing a better prognosis. The proposed phase-1 study will explore the safety and efficacy of escalated doses of oral Folinic acid concomitantly with Stupp regimen. To determine the MTD is the main objective of the study, then the toxicty profile, the RDP2 and the methylation process efficacy at the MGMT gene level.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 24
• Est. completion date: April 16, 2021
• Est. primary completion date: December 12, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Operated GBM (complete or near complete resection)
• Un-methylated MGMT gene

Exclusion Criteria:

• Non operable GBM
• Methylated MGMT

Related Conditions & MeSH terms

• Astrocytoma
• Glioblastoma
• Grade IV Astrocytoma

Intervention

Drug:
• Temozolomide
All the Patients are treated by oral Temozolomide 75 mg/m²/day every day during 42 days, 30 minutes after Folinic acid and 120 min before the radiation dose to the brain tumor. After one month rest, the maintenance phase consists of:Temozolomide is given orally (30 min after Folinic acid), at 200 mg/m²/day every day during 5 days: one course every month during 6 months (6 maintenance course).
• folinic acid at pharmacological dose is the escalated drug

Radiation:
• High voltage radiation therapy (linear accelerator)
Brain tumor field is irradiated Five days a week, during Stupp regimen during 6 weeks. During the sams time, Folinic acid and Temozolomide are given orally every days (six weeks).

Locations

Country	Name	City	State
France	Institut de Cacerologie de l'ouest - site Paul Papin	Angers
France	CHU de Lyon	Bron
France	ICO site Gauducheau	Nantes
France	CLCC Antoine Lacassagne	Nice

Sponsors (3)

Lead Sponsor	Collaborator
Institut Cancerologie de l'Ouest	Centre Antoine Lacassagne, Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

References & Publications (1)

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Progression-free survival (PFS)	Progression-free survival (PFS)	Year 1
Other	Folic acid and Temozolomide combination Toxicity evaluation	Acute toxicity: Common toxicity criteria version 4.03	day 43
Primary	Maximal Tolerated Dose	maximal tolerated dose 3x3 patients inclusion(modified Fibonnacci dose escalation )	day 43
Secondary	MGMT gene re-methylation	MGMT gene re-methylation in tumoral and blood samples	day 43