NOX-A12 Plus Bevacizumab and Radiotherapy Shows Sustained Survival in Glioblastoma

The addition of the CXCL12 inhibitor NOX-A12 (olaptesed pegol) to standard frontline therapy with radiation and bevacizumab (Avastin) led to an overall survival (OS) rate of 83% (n = 5/6) at a median follow-up of 15 months in patients with glioblastoma, according to data from an expansion arm of the phase 1/2 GLORIA trial (NCT04121455).¹

The announcement follows the green light from the Data Safety and Monitoring Board in January 2022 to resume enrollment to this arm of the trial following confirmation of safety of the regimen.²

“Reaching the 15-month [OS] point with this expansion arm is a significant milestone in our development of NOX-A12 in glioblastoma, and to do so with more than 80% of patients still on study represents a fantastic achievement,” Aram Mangasarian, chief executive officer of TME Pharma, said in a press release. “This latest set of survival data further underlines the clinically meaningful improvement that this treatment combination of NOX-A12, radiotherapy, and bevacizumab could bring over the current standard of care for this challenging indication with extremely poor prognosis. We are building an enviable clinical profile around our lead asset in glioblastoma, which strengthens NOX-A12’s position for potential partnering and our coming discussions with regulators regarding the pathway to market.”

Preclinical data show that inhibiting the CXCL12/CXCR4/CXCR7 axis prevents the collection of pro-vasculogenic bone marrow-derived cells after radiotherapy and keeps T cells from the tumor microenvironment.³

In 2014, the FDA granted an orphan drug designation to NOX-A12 for use in combination with radiation for the treatment of patients with glioblastoma.⁴

The expansion portion of the GLORIA trial enrolled patients at least 18 years of age with newly diagnosed, histologically confirmed, supratentorial World Health Organization grade IV glioblastoma, with unmethylated MGMT promoter status; an ECOG performance status between 0 and 2; an estimated minimum life expectancy of 3 months; and a stable or decreasing dose of corticosteroids during the week before inclusion on the trial.⁵

In arm A, patients received 600 mg of intravenous NOX-A12 weekly for 26 weeks, plus 10 mg/kg of bevacizumab every 2 weeks for 26 weeks and radiotherapy at a cumulative dose of 60 Gy in 2 fractions during weeks 1 through 6 in patients with incomplete or no resection.

In arm B, the same dose and schedule of NOX-A12 and radiotherapy was administered to patients with complete resection. In arm C, pembrolizumab (Keytruda) replaced bevacizumab and was evaluated in combination with NOX-A12 and radiotherapy in incompletely resected patients.

The primary end point of the trial is safety. Key secondary end points include 6-month progression-free survival (PFS), median PFS, median OS, tumor vascularization as per vascular MRI, plasma level of NOX-A12, neurologic function, and quality of life.

Findings from the dose-escalation portion of the trial, which were previously published in the Journal of Clinical Oncology, showed that the combination of NOX-A12 and radiotherapy was well tolerated and safe.³

Of all grade 2 or greater adverse effects (AEs; n = 77), 3 (4%) were deemed to be related to NOX-A12, including 1 grade 3 AE at dose level 3. No dose-limiting toxicities or treatment-related deaths occurred with the combination.

Regarding efficacy, 89% (n = 8/9) of patients with target lesions at baseline showed a target lesion response during treatment, and 4 patients (40%) achieved partial remission (PR) per radiologic mRANO criteria (n = 2 at dose level 1; n = 2 at dose level 3). All 3 patients treated at dose level 1 and all 4 treated at dose level 3 experienced PR in at least 1 non–target lesion. Additionally, at least 1 non–target lesion was eradicated in 3 cases (n = 2 at dose level 1; n = 1 at dose level 3).

Additionally, NOX-A12 was associated with dose dependent activity, with the best radiographic responses of non–target lesions (dose level 1, +49.5; dose level 2, +488.3; dose level 3, –59%), highest increase in diffusion (mean apparent diffusion coefficient increase: +46.4; +28.2; +56.7%), and largest decrease in the fraction of highly-perfused tumor at the highest dose level (mean: –33.5; –32.8; –47.7%). 

References

1. TME Pharma announces positive 15-month survival data from GLORIA expansion arm evaluating NOX-A12 in combination with radiotherapy and bevacizumab in glioblastoma. News release. June 28, 2023. Accessed June 29, 2023. https://www.businesswire.com/news/home/20230627353547/en/TME-Pharma-Announces-Positive-15-month-Survival-Data-From-GLORIA-Expansion-Arm-Evaluating-NOX-A12-in-Combination-With-Radiotherapy-and-Bevacizumab-in-Glioblastoma
2. NOXXON provides progress update on the expansion arms of the phase 1/2 GLORIA trial with NOX-A12 in brain cancer patients. News release. NOXXON Pharma N.V.; January 7, 2022. Accessed June 29, 2023. http://www.tmepharma.com/downloads/pressrel/2022-01-07_Update_GLORIA_Expansion_Arms_EN.pdf
3. Giordano FA, Layer JP, Leonardelli S, et al. Radiotherapy and olaptesed pegol (NOX-A12) in partially resected or biopsy-only MGMT-unmethylated glioblastoma: Interim data from the German multicenter phase 1/2 GLORIA trial. J Clin Oncol. 2022;40(suppl 16):2050. doi:10.1200/JCO.2022.40.16_suppl.2050
4. NOXXON Spiegelmer receives FDA orphan drug designation for glioblastoma treatment. News release. NOXXON Pharma N.V.; September 23, 2014. Accessed June 29, 2023. http://www.tmepharma.com/downloads/pressrel/2014-09-23_NOXXON_NOXA12_receives_ODD.pdf
5. Glioblastoma treatment with irradiation and olaptesed pegol (NOX-A12) in MGMT unmethylated patients (GLORIA). ClinicalTrials.gov. Updated June 22, 2023. Accessed June 29, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04121455