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The Data Safety Monitoring Board has determined that it is safe and appropriate to continue recruitment to the expansion arm of the phase 1/2 GLORIA trial, which is examining a novel combination comprised of NOX-A12, radiotherapy, and bevacizumab in glioblastoma and incomplete tumor resection.
The Data Safety Monitoring Board has determined that it is safe and appropriate to continue recruitment to the expansion arm of the phase 1/2 GLORIA trial (NCT04121455), which is examining a novel combination comprised of NOX-A12 (olaptesed pegol), radiotherapy, and bevacizumab (Avastin) in patients with glioblastoma and incomplete tumor resection.1
The decision followed an evaluation of safety findings from the first 4 weeks of treatment in the first patient enrolled to arm B. Investigators will now continue to recruit 5 additional patients to this arm in accordance with trial protocol.
The German Federal Institute for Drugs and Medical Devices has also given the green light to the launch of the third expansion arm of the trial, which is slated to examine NOX-A12 in combination with radiotherapy and pembrolizumab (Keytruda) in patients with glioblastoma and incomplete tumor resection.
“The 3 arms in the expansion phase of our phase 1/2 study of NOX-A12 are supported by the clinical data from the GLORIA trial and are designed to explore the potential for improved benefits for patients with brain tumors,” Aram Mangasarian, chief executive officer of NOXXON Pharma N.V., stated in a press release. “The combination with the anti–PD-1 inhibitor pembrolizumab is of particular interest as we expect this combination therapy to unlock a stronger and more durable immune response against the tumor…We plan to use clinical data from the expansion arms to support our future pivotal glioblastoma study.”
NOX-A12 was developed to target the key chemokine protein CXCL12. In cancer, this chemokine protein serves as a communication bridge between tumor cells and the environment, and is known to encourage tumor proliferation, the formation of new blood vessels and metastasis, and to reduce cell death.2 The novel agent binds to 2 key sites within the protein to disrupt activity and target them for elimination.
The investigational agent was developed to attack solid tumors by modulating the tumor microenvironment. By enabling anticancer immune cells to enter the tumor, the agent can help to unleash the full potential of immunotherapy treatment approaches like checkpoint inhibitors. Moreover, the agent can prevent the attraction of repair cells to tumors by hindering tumor regrowth after radiotherapy.
To be eligible for enrollment to the expansion portion of the GLORIA trial, patients needed to have newly diagnosed, histologically confirmed, supratentorial World Health Organization grade IV glioblastoma and be at least 18 years of age.3
Moreover, patients needed to have unmethylated MGMT promoter status, a maximum ECOG performance status of 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.
If patients had a history of other cancers, a secondary malignancy that was active, planned hypofractionated radiotherapy, or clinically significant or uncontrolled cardiovascular disease, they were excluded. Other exclusion criteria included having previously received radiotherapy to the head, having received any other prior or concomitant investigational treatments for glioblastoma, or if they received chemotherapy within the past 5 years.
In arm B, participants were administered NOX-A12 at a weekly, continuous dose of 600 mg for the duration of 26 weeks. Radiotherapy was given in weeks 1 through 6 at a cumulative dose of 60 Gy in 2 Gy fractions, and bevacizumab was given at a dose of 10 mg/kg every 2 weeks for 26 weeks.
The 3 expansion arms of the trial intend to enroll 6 patients each. In addition to arms B and C, arm A is evaluating the combination of NOX-A12 and radiotherapy in patients with glioblastoma and complete tumor resection. In this arm, patients received NOX-A12 at 600 mg continuously for 26 weeks, and radiotherapy during weeks 1 through 6 at a cumulative dose of 60 Gy in 2 Gy fractions.
The primary outcome measure for the trial is safety. Key secondary outcome measures include progression-free survival (PFS) at 6 months, median PFS, median overall survival (OS), tumor vascularization as per vascular MRI, plasma level of NOX-A12, neurologic function, and quality of life.
Previously, NOX-A12 was evaluated in combination with pembrolizumab as a treatment for patients with microsatellite-stable (MSS), metastatic colorectal cancer (CRC) and pancreatic cancer with liver metastases, as part of the phase 1/2 OPERA study (NCT03168139).4 The key objective of this research was to determine whether CXCL12 inhibition with the agent could reverse the immune privileged status of the tumor microenvironment and thus broaden the applicability of checkpoint inhibitors to this population.
A total of 20 patients were recruited to the trial; of these patients, 11 had metastatic CRC and 9 had metastatic pancreatic cancer. Across the subsets, 15 patients were male (75%), and all had stage IV disease at the time of study entry. The mean age among those with CRC was 63 years (range, 55-73); among those with pancreatic cancer, the mean age was 67 years (range, 48-82).
The mean number of prior lines of systemic treatment received in those with CRC and pancreatic cancer was 5 (range, 2-9) vs 3 (range, 1-5), respectively. Moreover 9 vs 3 patients, respectively, previously underwent surgery. Among those with CRC, the best response achieved with last treatment was disease progression in 10 patients and stable disease in 1 patient. In the pancreatic cancer subset, the best response achieved with last treatment was disease progression for all patients. Investigators noted that because all patients had MSS disease, they should not be responsive to anti–PD-1 therapy.
Study participants were given 300 mg of NOX-A12 on days 1, 4, 8, and 11 of the monotherapy phase of the trial. Investigators did needle biopsies from acceptable liver metastases prior to treatment and on day 14. Samples were evaluated for immune cell infiltration per immunohistochemistry and cytokine signature.
Following the single-agent phase, participants were administered a combination of NOX-A12 at 300 mg and pembrolizumab at 200 mg every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. Investigators monitored progression via MRI every 8 weeks.
The doublet was found to induce immune response in this population. Twenty-five percent of patients had stable disease. The combination was also noted to prolong time on treatment for 35% of patients compared with previous therapy. The median PFS was 1.87 months. The 6-month OS rate was 39%; at 12 months, this rate was 20%. Three of the patients who had stable disease (15%) were noted to have survived for longer than 1 year.
In September 2014, the FDA granted an orphan drug designation to NOX-A12 in conjunction with radiotherapy in the treatment of patients with glioblastoma.5