370MO - FOLAGLI: A phase I study of folinic acid combined with temozolomide and radiotherapy to modulate MGMT gene promoter methylation in newly diagnosed MGMT non-methytated glioblastoma

Background

Glioblastoma is a very aggressive disease with a poor prognosis. The MGMT gene encodes an enzyme involved in DNA repair, the epigenetic silencing (by methylation) of which confers a better prognostic for GBM patients. We hypothesized that administration of folic acid could restore a methylation of MGMT promoter gene in non-methylated GBM and thus increase sensitivity to temozolomide combined with radiotherapy.

Methods

FOLAGLI is a non-randomized, phase 1 open study, with dose escalation (3+3 design) and expansion cohort of folic acid in combination with temozolomide and radiotherapy for newly diagnosed glioblastoma harboring non-methylated MGMT gene promoter detected by semi quantitative methyl-specific PCR. The study assessed the tolerability, pharmacodynamics and efficacy of folic acid dose escalation from 5 to 60 mg daily, given 30 minutes before temozolomide.

Results

Between March 2013 and March 2019, 90 patients were screened of whom 66 had a MGMT promoter methylated tumor. Finally, 24 patients were enrolled and one patient withdrew his consent. Median age was 56 years old [range 42-73]. No dose limiting toxicity was reported in the phase I part. The recommended dose for the expansion phase was 60 mg. Grade 1-2 treatment-related adverse events (AEs) occurring in ≥2 patients included asthenia (n=6), lymphopenia (n=2), nausea (n=3) and vomiting (n=3), alopecia (n=2) and anemia (n=2). Grade III AEs related to treatment occurring in ≥1 patients included lymphopenia (n=2), thrombocytopenia (n=1), neutropenia (n=1), dehydration (n=1) and hypoacousia (n=1). No grade IV AES occurred. With a median follow-up of 18.3 [8.5-65.5] months, median progression free survival (PFS) was 7.9m [7.1-8.3]. The median overall survival (OS) was 17.1m [12.6-24.5] and 6, 12 and 24 months OS rate were 100%, 79.8% [54.6-91.9] and 28.2 [9.2-51.2] respectively. For the eight patients with ctDNA monitoring, the combination of folic acid with temozolomide showed restoration of methylation on of the promoter of MGMT detected in ctDNA.

Conclusions

Preliminary safety and efficacy results suggest that folic acid combined with temozolomide and radiotherapy is well tolerated and feasible.

Clinical trial identification

NCT01700569.

Editorial acknowledgement

Legal entity responsible for the study

Institut de Cancerologie de L'Ouest.

Funding

Institut National du Cancer.

Disclosure

All authors have declared no conflicts of interest.