NanO2 Plus Radiation/Temozolomide Is Under Exploration in Newly Diagnosed Glioblastoma

Michael Badruddoja, MD

Early safety data from the phase 2b RESTORE study (NCT03862430) examining NanO₂, a high-capacity oxygen carrier, combined with radiation and temozolomide (Temodar) in patients with newly diagnosed glioblastoma were shared during the 2024 Society for Neuro-Oncology Annual Meeting.¹

The most common non-serious adverse effects (AEs) observed in patients who had been enrolled to the trial by the August 2024 data cutoff (n = 22) were of the following system organ classes: nervous system; general disorders; gastrointestinal; respiratory, thoracic; skin, subcutaneous; infections; injury; investigations; musculoskeletal; vascular; psychiatric; metabolism; eye; ear, labyrinth; renal, urinary; blood, lymphatic; and endocrine.

“This study is ongoing, assessing the safety and potential efficacy of NanO₂ in improving treatment outcomes for glioblastoma by enhancing oxygen delivery to hypoxic tumor regions,” Michael A. Badruddoja, MD, of the Center for Neurosciences in Tucson, Arizona, and colleagues, wrote in a poster shared during the meeting.

Glioblastoma is known to have extensive hypoxic regions, and cell death resulting from radiation relies on oxygen-free radicals and oxygen fixation of DNA strand breaks. When oxygen is absent, cancer cells are able to repair those breaks, which results in treatment resistance. Moreover, hypoxic cells are also known to be resistant to chemotherapy because of reduced drug efficacy, limited diffusion, and poor delivery to distant cells. As such, investigators hypothesized that using NanO₂ to boost oxygen delivery to hypoxic glioblastoma tissue would enhance the efficacy derived from chemoradiation.

RESTORE was a double-blind, prospective, placebo-controlled trial that enrolled patients with historically confirmed, newly diagnosed primary or secondary glioblastoma multiforme who were at least 18 years of age.² They were required to have a Karnofsky performance status of at least 70, a life expectancy of at least 3 months, and acceptable hematologic, renal, and hepatic function. Those with recurrent glioblastoma who received prior therapy for their disease apart from surgical resection were excluded.

Patients receive standard chemoradiation comprised of 30 fractions of focal radiation with 60 Gy given as 2 Gy fractions 5 days per week for 6 weeks with temozolomide concurrently given at 75 mg/m² for 6 weeks.¹ They were randomly assigned 1:2 to receive placebo or infusion with NanO₂ given immediately before each dose of radiation. During infusion and radiation patients continuously breathed oxygen. After 6 weeks of radiation and temozolomide, patients stopped treatment for 4 weeks prior to receiving temozolomide in the adjuvant setting.

Of the total 34 patients consented, 11 did not undergo random assignment due to screen failure (n = 8) or withdrawn consent (n = 3). Twenty-three patients comprised the randomly assigned intention-to-treat (ITT) group and only 1 patient did not receive treatment. The remaining 22 patients represented the treated safety set of the ITT. Four patients went off study; 1 withdrew and 3 died. A total of 18 patients remained on study at the time of data cutoff.

Of the 22 patients enrolled as of August 2024, 63.6% are MGMT unmethylated and 36.4% are unmethylated. Eighteen patients continued to be followed through maintenance treatment and long-term follow-up. The mean patient age was 62.9 years (range, 39-77). In terms of ethnicity, 18.2% of patients were Hispanic or Latino, 72.7% were not Hispanic or Latino, and 9.1% did not have this information known or specified. Most patients were White (95.5%).

Per site, 14 serious treatment-emergent AEs (TEAEs) were determined not related to study medication; 3 were unlikely, 1 was possibly, and 2 were probably related. Per medical monitor, 15 serious TEAEs were not considered related to study treatment; 3 were unlikely and 2 were possibly related. Two serious TEAEs were unlikely to be related to radiation, 4 were probably related, and 14 were not related. Six serious TEAEs were deemed unlikely to be related to temozolomide and 13 were not related; 1 was considered to have a causal relationship to the drug. A causal relationship of serious TEAEs with disease progression was noted in 4 patients.

The trial is ongoing with an estimated completion of September 2025.³

References

1. Badruddoja MA, Placencia C, Stea B, et al. A phase 2 double-blind, randomized, prospective, placebo controlled study of NanO2 combined with radiation and temozolomide in patients with newly-diagnosed glioblastoma: RESTORE. Presented at: 2024 SNO Annual Meeting; November 21-24, 2024; Houston, TX. CTNI-30.
2. Johnson JLH, Unger E. A phase 2 double-blind, randomized, prospective, placebo controlled study of NanO2 TM combined with radiation and temozolomide in patients with newly-diagnosed glioblastoma multiformE: RESTORE. Br J Cancer. 2024;7(2):694-715. doi:10.31488/bjcr.195
3. A study of NanO2TM combined with radiation and temozolomide in patients with newly diagnosed GBM (RESTORE). ClinicalTrials.gov. Updated October 1, 2024. Accessed November 22, 2024. https://clinicaltrials.gov/study/NCT03862430