Phase I/II study of maintenance therapy with metformin and temozolomide for newly diagnosed glioblastoma.

2051 Background: Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. A potential strategy for overcoming therapeutic resistance involves the development of novel therapies that target cancer stem/initiating cells. Our previous research demonstrated that metformin (MF), an antidiabetic drug, induces the differentiation of stem-like glioma-initiating cells and suppresses tumor formation via AMPK-FOXO3 activation (Stem Cells Transl Med, 2012). We conducted a phase I/II study to evaluate the clinical efficacy of MF combined with standard maintenance temozolomide (TMZ). Our phase I findings indicated that MF at doses of up to 2,250 mg/day combined with maintenance TMZ was well tolerated (Cancers, 2022). Here, we present the complete results of the phase I/II study. Methods: Patients aged 20–74 years with supratentorial GBM, Karnofsky Performance Status ≥ 70, and a history of initial chemoradiotherapy with TMZ were eligible. During the phase II study, patients received MF monotherapy for 14 days, followed by six 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 (target; one-sided alpha 10%, power 70%, threshold 1-year PFS, 27%; expected 1-year PFS, 50%, based on the historical EORTC/NCIC study (Stupp et al, 2005)). Results: From 2021–2023, 22 patients were enrolled in 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). According to the WHO 2016 classification, the initial histology 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%). Conclusions: Maintenance therapy with 2,250 mg/day of 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. Clinical trial information: jRCTs031200326 .