Background: Evidence is increasing for altered immune responses in malignant gliomas. Tumor-associated microglia/macrophages infiltrate human glioma tissue and produce cytokines that promote glioma growth, invasion and angiogenesis. Dimethyl fumarate (DMF), approved for relapsing-remitting multiple sclerosis, is toxic to in vitro activated microglial cells. Based on pre-clinical data demonstrating synergism with radiation (RT) and temozolomide (TMZ), we conducted a phase I study of DMF in patients with newly-diagnosed glioblastoma (GBM) in combination with RT and TMZ. Methods: Using a standard 3+3 dose escalation design (3 dose levels: 120 mg bid, 240 mg bid and 240 mg tid), newly-diagnosed GBM patients received daily DMF with RT (60 Gy) and concurrent TMZ 75 mg/m2 daily, followed by adjuvant DMF (continuously) and TMZ for up 6 maintenance cycles (150-200 mg/m2 on days 1-5 of each 28 day cycle). The maximum tolerated dose (MTD) was defined as the dose with ≤ 1/6 dose-limiting toxicities (DLT). The MTD was determined by evaluation of DLTs during the first 6 weeks of therapy. Results: Twelve patients were treated at the three dose levels, and no DLT was identified. There were no unexpected toxicities. The most common toxicities were lymphopenia (11 grade 3/4 events) and thrombocytopenia (2 grade 3/4 events). The only grade 3/4 non-heme toxicity was a grade 3 hemorrhoid event. Of the 12 evaluable patients, one remains on active treatment in maintenance phase. Three patients completed all treatment (concurrent and maintenance) with stable disease. Two patients had a partial response (RANO criteria) but then experienced disease progression during maintenance. Five patients had disease progression during study treatment and one patient chose to withdraw from the study during maintenance. Conclusions: These data suggest that DMF may be safely combined with RT and TMZ in GBM patients. A phase II study is under consideration. Clinical trial information: NCT02337426