A phase 2 double-blind, randomized, prospective, placebo-controlled study of NanO₂ combined with radiation and temozolomide in patients with newly diagnosed glioblastoma: RESTORE.

Abstract

2065 Background: Glioblastoma (GBM) contains extensive hypoxic regions due to tumor-associated thrombosis and abnormal vasculature. Hypoxia drives resistance to radiation (RT) and temozolomide (TMZ) by limiting oxygen-dependent DNA damage, enabling DNA repair, and reducing drug efficacy and delivery. The RESTORE trial (NCT03862430) is the first randomized, prospective, placebo-controlled study of NanO₂ (2% w/v dodecafluoropentane emulsion) in GBM, a fluorocarbon-based oxygen therapeutic hypothesized to reoxygenate hypoxic GBM tissue, with the goal of enhancing the efficacy of chemoradiation. Methods: Patients with newly diagnosed GBM (WHO 2021) received standard-of-care radiation (60 Gy) with concurrent TMZ (75 mg/m²/day). Patients were randomized 2:1 to receive either NanO 2 or 0.9% sodium chloride administered intravenously immediately prior to each RT fraction, with continuous supplemental oxygen given during the infusion and RT. Following chemoradiation, patients completed a four-week recovery period before initiating adjuvant TMZ for 6 cycles. The primary endpoint is progression free survival and secondary endpoints include overall survival, objective response rate, pseudoprogression rate, and patient reported outcomes. Results: Between May 2023 and October 2025, 93 patients were treated (safety set). The study has completed the planned enrollment. Median age was 63 years (range, 19–84) and 57% were men. As of the data cutoff on 12/29/25, all patients completed the follow up visit 4 weeks after chemoradiation. Sixty-eight patients (73%) remained on study undergoing adjuvant TMZ or in long-term follow-up. Twenty-one patients passed of tumor progression and 4 patients withdrew consent. The median duration on study was 8.7 months (range, 1.3–31.4). During chemoradiation and the four-week recovery, 63 treatment-emergent adverse events (TEAEs) of CTCAE severity grade ≥3 were reported in 37% of patients, with brain edema, lymphocyte count decreased, and platelet count decreased being the most frequently reported. Twenty-six treatment-emergent serious adverse events (TESAEs) occurred in 19% of patients, with embolism, pulmonary embolism, and seizure being the most frequently reported. Three TESAEs were assessed as possibly or probably related to study drug; none were unexpected. Survival follow up is ongoing. Conclusions: In this blinded, pooled safety analysis of a randomized phase 2 trial in newly diagnosed GBM, the study treatment was well tolerated and no new safety signals were identified. Treatment allocation remains blinded. Efficacy outcomes and arm-specific safety analyses will be reported after completion of the primary endpoint analysis. Clinical trial information: NCT03862430 .