ACT-19 A REPORT OF PHASE I PART OF PHASE I/II STUDY OF MAINTENANCE THERAPY WITH METFORMIN AND TEMOZOLOMIDE FOR GLIOBLASTOMA

Abstract

Abstract Background Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. One strategy for overcoming resistance is developing a new therapy targeting the cancer stem/initiating cells. We have shown that the antidiabetic drug metformin (MF) can induce differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. We conducted a phase I/II study to examine the clinical effect of MF combined with standard maintenance temozolomide (TMZ). Here, we report the result of phase I part and the current status of phase II part. Patients and Methods Patients between 20 and 74 years of age with supratentorial GBM histologically diagnosed according to the World Health Organization 2016 classification were eligible. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first 6 weeks after MF initiation. Results Between February 2021 and January 2022, the first three patients were treated with 1,500 mg/day MF and the next four patients were treated with 2,250 mg/day MF, which is the maximum dose approved in Japan. The median age of the patients was 41 years. Three tumors (42.9 %) were IDH1/2 mutants and 4 (57.1 %) were IDH1/2 wild-types. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, which were observed in three patients. All of them were manageable, with grade 1 or 2. Only one grade 3 seizure was reported, which was likely related to the tumor. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up. Conclusion MF dose of up to 2,250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to phase II study with 2,250 mg/day MF.