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

NCT01700569 — Phase 1, Terminated, 24 participants, Institut Cancerologie de l'Ouest

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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.

Registry	NCT01700569, acronym FOLAGLI
Status	Terminated - changing the standard of care
Phase	Phase 1
Study type	Interventional; na, single group, masking: none, treatment
Enrollment	24 (Actual)
Sponsor	Institut Cancerologie de l'Ouest (Other); collaborators: Centre Antoine Lacassagne, Hospices Civils de Lyon
Conditions	Grade IV Astrocytoma, Glioblastoma
Interventions	Temozolomide, folinic acid at pharmacological dose is the escalated drug, High voltage radiation therapy (linear accelerator) (Drug, radiation)
Dates	start 2013-01-01, primary completion 2019-12-12, completion 2021-04-16, first posted 2012-10-04, last updated 2023-02-21
Locations	4 sites in France

-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.

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+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.

+Arms and interventions

Arm	Type	Interventions	Description
Folinic Acid	Experimental	Drug: Temozolomide; Drug: folinic acid at pharmacological dose is the escalated drug; Radiation: 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.

Temozolomide (Drug), also known as Temodal, capsule dosage available: 5, 20, 10, 180 and 250 mg: 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 (Drug), also known as Folinate de Calcium, Lederfoline
High voltage radiation therapy (linear accelerator) (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).

+Outcome measures

Primary outcomes

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

Secondary outcomes

MGMT gene re-methylation [day 43]: MGMT gene re-methylation in tumoral and blood samples

Other outcomes

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

+Eligibility

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

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

Exclusion Criteria:

* Non operable GBM
* Methylated MGMT

+Locations (4)

Facility	City	Country
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

+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. doi: 10.1056/NEJMoa043330. PMID 15758009

+Investigators

Mario CAMPONE, MD, PhD, Principal investigator, Institut Cancerologie de l'Ouest