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

• ClinicalTrials.gov Identifier: NCT01700569
• Recruitment Status: Recruiting
• First Posted: October 4, 2012
• Last Update Posted: May 14, 2019
• Sponsor: Institut Cancerologie de l'Ouest
• Collaborators: Centre Antoine Lacassagne; Hospices Civils de Lyon
• Information provided by (Responsible Party): Institut Cancerologie de l'Ouest

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Grade IV Astrocytoma; Glioblastoma	Drug: Temozolomide; Drug: folinic acid at pharmacological dose is the escalated drug; Radiation: High voltage radiation therapy (linear accelerator)	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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.
• Study Start Date: January 2013
• Estimated Primary Completion Date: September 2020
• Estimated Study Completion Date: September 2021

Arms and Interventions

Arm

Intervention/treatment

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.

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).; Other Names: Temodal; capsule dosage available: 5, 20, 10, 180 and 250 mg; Drug: folinic acid at pharmacological dose is the escalated drug; Other Name: Folinate de Calcium, Lederfoline; 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).

Outcome Measures

Primary Outcome Measures :

1. Maximal Tolerated Dose [ Time Frame: day 43 ]
   maximal tolerated dose 3x3 patients inclusion(modified Fibonnacci dose escalation )

Secondary Outcome Measures :

1. MGMT gene re-methylation [ Time Frame: day 43 ]
   MGMT gene re-methylation in tumoral and blood samples

Other Outcome Measures:

1. Progression-free survival (PFS) [ Time Frame: Year 1 ]
   Progression-free survival (PFS)
2. Folic acid and Temozolomide combination Toxicity evaluation [ Time Frame: day 43 ]
   Acute toxicity: Common toxicity criteria version 4.03

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

• Non operable GBM
• Methylated MGMT

Contacts and Locations

Contacts

Contact: Nadia FLEURY, PhD; +33240679900 ext 9168; nadia.fleury@ico.unicancer.fr

Locations

France

Institut de Cacerologie de l'ouest - site Paul Papin; Recruiting

Angers, France, 49055

Contact: Patrick SOULIÉ, MD +33241352700 Patrick.soulie@ico.unicancer.fr

Principal Investigator: Patrick SOULIÉ, MD

Sub-Investigator: Paule AUGEREAU, MD

Sub-Investigator: Eric JADAUD, MD

Sub-Investigator: Amaury PAUMIER, MD

Sub-Investigator: Julien BLANCHECOTTE, MD

Sub-Investigator: Florence LEGOUTE, MD

Sub-Investigator: Margot NOBLECOURT, MD

CHU de Lyon; Recruiting

Bron, France, 69677

Contact: François DUCRAY, MD 04 72 35 78 06 Francois.ducray@chu-lyon.fr

Principal Investigator: François DUCRAY, MD

Sub-Investigator: Stéphanie CARTALAT -CAREL, MD

Sub-Investigator: Laure THOMAS-MAISONNEUVE, MD

Sub-Investigator: Jérôme HONNORAT, MD

Sub-Investigator: Ciprian ENACHESCU, MD

Sub-Investigator: Anne D'HOMBRES, MD

ICO site Gauducheau; Recruiting

Nantes, France, 44805

Contact: Mario Campone, MD, PhD +33240679900 mario.campone@ico.unicancer.fr

Principal Investigator: Mario CAMPONE, MD, PhD

Sub-Investigator: Jean S FRESNEL, MD

Sub-Investigator: Maud AUMONT, MD

Sub-Investigator: Carole GOURMELON, MD

Sub-Investigator: Marie ROBERT, MD

Sub-Investigator: Augustin MERVOYER, MD

Sub-Investigator: Pauline DU RUSQUEC, MD

Sub-Investigator: Audrey ROLLOT, MD

Sub-Investigator: Judith RAIMBOURG, MD

Sub-Investigator: Mathilde COLOMBIE, MD

Sub-Investigator: Emmanuel JOUGLAR, MD

Sub-Investigator: Akila BENINE -DANDEC, MD

CLCC Antoine Lacassagne; Not yet recruiting

Nice, France, 06189

Contact: Esma SAADA-BOUZID, MD +334 92 03 10 00 esma.saada-bouzid@nice.unicancer.fr

Principal Investigator: Esma SAADA-BOUZID, MD

Sub-Investigator: Véronique MARI, MD

Sponsors and Collaborators

Institut Cancerologie de l'Ouest

Centre Antoine Lacassagne

Hospices Civils de Lyon

Investigators

• Principal Investigator: Mario CAMPONE, MD, PhD; Institut Cancerologie de l'Ouest

More Information

Publications:

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.

• Responsible Party: Institut Cancerologie de l'Ouest
• ClinicalTrials.gov Identifier: NCT01700569
• Other Study ID Numbers: ICO 2012-02; 2012-000774-31 ( EudraCT Number )
• First Posted: October 4, 2012
• Last Update Posted: May 14, 2019
• Last Verified: April 2019

Keywords provided by Institut Cancerologie de l'Ouest:

high-grade; glioma; epigenetic

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Leucovorin; Folic Acid; Temozolomide; Levoleucovorin; Physiological Effects of Drugs; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antidotes; Protective Agents; Vitamin B Complex; Vitamins; Micronutrients; Nutrients; Growth Substances; Hematinics