Metformin with Temozolomide for Newly Diagnosed Glioblastoma: Results of Phase I Study and a Brief Review of Relevant Studies

SIMPLE SUMMARY: Glioblastoma is an incurable disease, demanding new therapeutic approaches. Our preclinical studies proved that the antidiabetic drug metformin could induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation, suggesting the potential of metformin for treating glioblastoma. Taking into consideration that the anti-cancer effects of metformin are known to be dose-dependent, we conducted a dose-escalation phase I study to evaluate the safety and determine the recommended phase II dose of metformin in combination with maintenance temozolomide in patients with newly diagnosed glioblastoma. We show that the 2250 mg/day metformin appeared to be well tolerated with acceptable toxicity. Therefore, we proceed to a phase II study with 2250 mg/day metformin to evaluate its clinical benefits. Cancer stem/initiating cells are resistant to existing radiotherapy or chemotherapy; thus, our strategy targeting glioma-initiating cells using metformin is a novel therapeutic strategy which could possibly improve the outcome of glioblastoma. ABSTRACT: Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. 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 session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF.