CTNI-75. SAFETY AND EFFICACY OF METFORMIN AND TEMOZOLOMIDE TARGETING CANCER STEM CELLS FOR NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Metformin (MF), an antidiabetic drug, induces the differentiation of stem-like glioma-initiating cells and suppresses tumor formation via AMPK-FOXO3 activation. Based on this theory, we conducted a phase I/II study to evaluate the clinical efficacy of MF targeting cancer stem cells combined with standard maintenance temozolomide (TMZ) for newly diagnosed glioblastoma (GBM) and present the complete results of the phase I/II study. PATIENTS AND METHODS Patients aged 20–74 years with supratentorial GBM, Karnofsky Performance Status ≥ 70, and a history of initial chemoradiotherapy with TMZ were eligible. Our phase I findings indicated that MF at doses of up to 2,250 mg/day combined with maintenance TMZ was well tolerated. During the phase II study, patients received MF monotherapy for 14 days, followed by 6 cycles of TMZ combined with daily MF (2,250 mg) for 365 days. The primary endpoint was the 1-year progression-free survival (PFS) rate from the initiation of chemoradiotherapy with TMZ RESULTS From 2021–2023, 22 patients were enrolled from 5 hospitals and 21 patients received TMZ combined with daily MF. The cohort included 12 men and nine women, with a median age of 50 years (32–69 years). The initial histology based on WHO 2016 classification revealed 18 IDH-wild-type and 3 IDH-mutant GBMs. The 1-year PFS was 47.6 % (90% CI; 29.2–64.0), achieving the primary endpoint. The 2-year overall survival rate was 54.5%. Grade ≥ 3 adverse events included lymphocytopenia (19%), thrombocytopenia (4.8%), appetite loss (4.8%), body weight loss (4.8%), nausea (4.8%), and seizures (4.8%). CONCLUSION Maintenance therapy with MF combined with TMZ for newly diagnosed GBM is promising. A phase III study comparing MF combined with TMZ vs. TMZ alone for the treatment of GBM is planned.