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

NCT ID: NCT01700569

Last Updated: 2023-02-21

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-31
• Study Completion Date: 2021-04-16

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.

Conditions

Grade IV Astrocytoma; Glioblastoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Temozolomide

Intervention Type: DRUG

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

Intervention Type: DRUG

High voltage radiation therapy (linear accelerator)

Intervention Type: RADIATION

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).

Interventions

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).

Intervention Type: DRUG

folinic acid at pharmacological dose is the escalated drug

Intervention Type: DRUG

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).

Intervention Type: RADIATION

Other Intervention Names

Temodal; capsule dosage available: 5, 20, 10, 180 and 250 mg; Folinate de Calcium, Lederfoline

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

• Non operable GBM
• Methylated MGMT

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centre Antoine Lacassagne

OTHER

Sponsor Role: collaborator

Hospices Civils de Lyon

OTHER

Sponsor Role: collaborator

Institut Cancerologie de l'Ouest

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mario CAMPONE, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Institut Cancerologie de l'Ouest

Locations

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

Countries

France

References

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.

Reference Type: BACKGROUND

PMID: 15758009 (View on PubMed)

Other Identifiers

2012-000774-31

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ICO 2012-02

Identifier Type: -

Identifier Source: org_study_id