Clinical trial NCT01700569: Phase-1 Study of Folinic Acid to Modulate MGMT Gene in Glioblastoma
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Grade IV Astrocytoma
Glioblastoma
Keywords: high-grade
glioma
epigenetic
Lead sponsor: Institut Cancerologie de l'Ouest
Sponsor class: OTHER
Collaborators: name: Centre Antoine Lacassagne
name: Hospices Civils de Lyon
First posted: 2012-10-04
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

* Non operable GBM
* Methylated MGMT

Primary outcomes:
measure: Maximal Tolerated Dose
timeFrame: day 43
Secondary outcomes:
measure: MGMT gene re-methylation
timeFrame: day 43
Other outcomes:
measure: Progression-free survival (PFS)
timeFrame: Year 1
measure: Folic acid and Temozolomide combination Toxicity evaluation
timeFrame: day 43
Locations:
city: Angers
country: France
facility: Institut de Cacerologie de l'ouest - site Paul Papin
city: Bron
country: France
facility: CHU de Lyon
city: Nantes
country: France
facility: ICO site Gauducheau
city: Nice
country: France
facility: CLCC Antoine Lacassagne
Study officials:
affiliation: Institut Cancerologie de l'Ouest
name: Mario CAMPONE, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.