Phase-1 Study of Folinic Acid to Modulate MGMT Gene in Glioblastoma (FOLAGLI)
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.
Grade IV Astrocytoma
Drug: folinic acid at pharmacological dose is the escalated drug
Radiation: High voltage radiation therapy (linear accelerator)
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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.|
- Maximal Tolerated Dose [ Time Frame: day 43 ] [ Designated as safety issue: Yes ]maximal tolerated dose 3x3 patients inclusion(modified Fibonnacci dose escalation )
- MGMT gene re-methylation [ Time Frame: day 43 ] [ Designated as safety issue: No ]
- Overall Survival [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
|Study Start Date:||January 2013|
|Estimated Study Completion Date:||October 2015|
|Estimated Primary Completion Date:||October 2014 (Final data collection date for primary outcome measure)|
Experimental: Folinic Acid
Folinic acid is given orally every day during the radiation therapy (47 days), then 5 days at each of the 6 maintenance cycle of temozolomide. The dose is escalated in a "3x3" method and the levels are: 5mg, 10mg, 15mg, 30mg, 60mg.
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).
Other Names:Drug: folinic acid at pharmacological dose is the escalated drug
Other Name: Folinate de Calcium, LederfolineRadiation: 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).
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01700569
|Contact: Francois PEIN, MDfirstname.lastname@example.org|
|ICO site Gauducheau||Recruiting|
|Nantes, France, 44805|
|Contact: Mario Campone, MD, PhD +33240679900 email@example.com|
|Principal Investigator: Mario CAMPONE, MD, PhD|
|Sub-Investigator: Jean S FRESNEL, MD|
|Principal Investigator:||Mario CAMPONE, MD, PhD||Institut Cancerologie de l'Ouest|