Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma.

Background: Dimethyl fumarate (DMF), an oral agent approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), has promising preclinical activity against glioblastoma (GBM). This phase I study sought to determine the recommended phase 2 dose (RP2D) of DMF and evaluate its safety and toxicity when combined with standard concurrent radiotherapy (RT) and temozolomide (TMZ) followed by maintenance TMZ in patients with newly diagnosed GBM.

Methods: Using a standard 3 + 3 dose-escalation design with 3 dose levels, patients received daily DMF with 60 Gy RT and concurrent TMZ 75 mg/m daily, followed by maintenance DMF (continuously) and TMZ 150-200 mg/m on days 1-5 of each 28-day cycle for up to 6 cycles. The maximum tolerated dose (MTD) was determined by evaluation of dose-limiting toxicity (DLT) during the first 6 weeks of therapy.

Results: Twelve patients were treated at the 3 dose levels, and no DLTs were observed. There were no unexpected toxicities. The most common grade 3/4 treatment related adverse events (AEs) were lymphopenia (58%), decreased CD4 count (17%), and thrombocytopenia (17%). Four patients completed all planned treatment; seven patients had progression on treatment. One patient chose to withdraw from the study during maintenance. The median progression-free survival (PFS) for all patients was 8.7 months with no difference in PFS between those with stable disease or a partial response; median overall survival was 13.8 months.

Conclusions: DMF may be safely combined with RT and TMZ in patients with newly diagnosed GBM. The RP2D for DMF is 240 mg three times daily.