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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Grade IV Astrocytoma, Glioblastoma

Intervention / Treatment
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* Drug: Temozolomide
* Drug: folinic acid at pharmacological dose is the escalated drug
* Radiation: High voltage radiation therapy (linear accelerator)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Operated GBM (complete or near complete resection) Un-methylated MGMT gene Exclusion Criteria: Non operable GBM Methylated MGMT

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Folinic Acid<br>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. | Drug: Temozolomide<br>* 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).<br>* Other names: capsule dosage available: 5, 20, 10, 180 and 250 mg;Drug: folinic acid at pharmacological dose is the escalated drug<br> <br> * Other names: Folinate de Calcium, Lederfoline;Radiation: High voltage radiation therapy (linear accelerator)<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Tolerated Dose | maximal tolerated dose 3x3 patients inclusion(modified Fibonnacci dose escalation ) | day 43 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MGMT gene re-methylation | MGMT gene re-methylation in tumoral and blood samples | day 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high-grade, glioma, epigenetic