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

Phase 1

Terminated

• Conditions: Grade IV Astrocytoma; Glioblastoma
• Interventions: Drug: Temozolomide; Drug: folinic acid at pharmacological dose is the escalated drug; Radiation: High voltage radiation therapy (linear accelerator)

• Registration Number: NCT01700569
• Lead Sponsor: Institut Cancerologie de l'Ouest

Brief 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.

Detailed 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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2012-09-12
• Study First Submitted QC: 2012-10-02
• Study First Posted: 2012-10-04
• Study Start: 2013-01
• Primary Completion: 2019-12-12
• Study Completion: 2021-04-16
• Status Verified: 2021-05
• Last Update Submitted: 2023-02-20
• Last Update Posted: 2023-02-21

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

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

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Exclusion Criteria

• Non operable GBM
• Methylated MGMT

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Folinic Acid	folinic acid at pharmacological dose is the escalated drug	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.
Folinic Acid	High voltage radiation therapy (linear accelerator)	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.
Folinic Acid	Temozolomide	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.

Primary Outcome Measures

Name	Time	Method
Maximal Tolerated Dose	day 43	maximal tolerated dose 3x3 patients inclusion(modified Fibonnacci dose escalation )

Secondary Outcome Measures

Name	Time	Method
MGMT gene re-methylation	day 43	MGMT gene re-methylation in tumoral and blood samples

Trial Locations

Locations (4)

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, France