CTNI-78. A phase 2 double-blind, randomized, prospective, placebo-controlled study of NanO₂TM combined with radiation and temozolomide in patients with newly diagnosed glioblastoma: RESTORE

Abstract INTRODUCTION Glioblastoma (GBM) has extensive hypoxic regions producing significant therapeutic resistance, Radiation (RT)-induced cell death relies on oxygen free radicals and oxygen fixation of DNA-strand breaks. In the absence of oxygen, tumor cells can repair the DNA single-strand breaks, leading to treatment resistance. Hypoxic cells also exhibit chemoresistance due to decreased drug efficacy, limited drug diffusion, and poor delivery to distant cells. This study hypothesizes that increasing oxygen delivery using NanO₂ (2% w/v dodecafluoropentane emulsion) infusion and inhaled oxygen will enhance the efficacy of chemoradiation. METHODS Patients with newly diagnosed GBM, planned to receive standard fractionated temozolomide (TMZ) chemoradiation (60 Gy) are eligible. Patients are randomized 2:1 to either NanO₂ or placebo infused immediately before each RT fraction. All patients continuously breathe 100% oxygen during infusion and RT. Post-completion of chemoradiation; patients receive monthly maintenance TMZ per Stupp et al (2005). The primary endpoint is progression free survival and key secondary endpoints are overall survival and objective response rate, with response assessments per mRANO criteria. RESULTS Sixty (60) patients have been enrolled to date. There have been 41 adverse events of CTCAE grade 3 or higher, with the most frequent being seizures, pulmonary embolism, fatigue, thrombocytopenia, and hemiparesis. One patient developed Grade 2 epistaxis, likely associated with oxygen administration. There were 11 deaths due to tumor progression. One patient withdrew consent in favor of best supportive care after treatment started. CONCLUSION This ongoing randomized trial is assessing the safety and potential survival benefit of NanO₂ in newly diagnosed GBM. By improving oxygen delivery to hypoxic tumor regions, NanO₂ may enhance the efficacy of chemoradiation. The study remains blinded, and no preliminary efficacy conclusions can be made at this time. Continued patient enrollment and follow-up will determine whether this approach improves key clinical outcomes, in comparison to patients receiving standard-of-care treatment.