CTNI-68. PHASE I/II STUDY OF MAINTENANCE THERAPY WITH METFORMIN AND TEMOZOLOMIDE FOR TARGETING GLIOBLASTOMA CANCER STEM CELLS

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 (Stem Cells Transl Med. 2012;1(11)). We conducted a phase I/II study to examine the clinical effect of MF combined with standard maintenance temozolomide (TMZ). Patients and METHODS Patients between 20 and 74 years of age with supratentorial GBM were eligible. MF dose-escalation study was performed using a 3 + 3 design as phase I part to determine recommended phase II dose. Dose-limiting toxicities (DLTs) were assessed during the first 6 weeks after MF initiation. After completing phase I study, we proceeded to phase II part. RESULTS The first three patients were treated with 1,500 mg/day MF from 2021 and the next four patients were treated with 2,250 mg/day MF, which is the maximum dose approved in Japan. 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 (Cancers (Basel). 2022;14(17)). Based on the phase I study, we proceeded to phase II study with 2,250 mg/day MF from April 2022 and finished recruiting patients for phase II part in May 2023. Primary endpoint of phase II trial is progression-free survival rate at 12 months compared to historical data. CONCLUSION MF dose of up to 2,250 mg/day combined with maintenance TMZ was well tolerated. We report the safety and efficacy of MF with TMZ for GBM.