Young, male, brain cancer patient wearing a hat/head covering is sitting in bed With a Toy Dog. Image signifies use of precision cancer therapy to improve outcomes.
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A candidate therapy being developed by U.S. biotech Chimerix shows good survival in patients with a specific type of glioma brain cancer in early clinical trials.

The treatment, ONC201 or dordaviprone, binds to the G-protein coupled dopamine receptor D2 and the mitochondrial protease ClpP.

Initial trials in glioblastoma (a type of glioma) patients were not successful, but the investigators noticed that the drug seemed to have a positive effect in a small group of patients with diffuse midline gliomas that contained the histone mutation H3K27M.

Based on these observations, new trials of the drug were set up to test its efficacy in this specific group of patients.

The current study, published in the journal Cancer Discovery, reports results from two early clinical trials testing dordaviprone in patients with diffuse midline gliomas and H3K27M mutations. These kinds of brain tumors occur mostly in children and young people and are aggressive and hard to treat, with overall survival predictions after diagnosis of 11–15 months.

“The H3K27M mutation is most frequently identified in pediatric and young adult gliomas located in midline central nervous system structures, where the thalamus and brainstem account for most patients carrying the mutation. Due to the location of these tumors, surgical resection is limited, and no effective systemic therapy has been identified to date,” write co-lead author Carl Koschmann, associate professor of pediatric neuro-oncology and clinical scientific director of the Chad Carr Pediatric Brain Tumor Center at Michigan Medicine, and colleagues.

One trial recruited 30 patients with a median age of eight years and the other recruited 41 with a median age of 24 years. Some patients were treated with dordaviprone following radiation, but prior to recurrence, and others after recurrence.

Patients in the trials who were treated with dordaviprone after initial radiation but before recurrence had a median overall survival of 21.7 months. Participants treated after a tumor recurrence had a median overall survival of 9.3 months. Overall, nearly a third of patients lived longer than two years.

When the researchers assessed mechanism of action, they found that dordaviprone was able to enter the tumor cells and influence the activity of the mitochondria in the cells. They also identified a biomarker of efficacy, L-2HG, produced by tumor cells in patients responding to the therapy.

“It’s an incredibly difficult tumor to treat. Prior to this study, there have been more than 250 clinical trials that have not been able to improve outcomes. This is a major crack in the armor,” said Koschmann in a press statement.

He conceded that the treatment is still not a cure for patients, but can significantly increase survival. “For now, we have this patient population that didn’t have a drug before, and now we see many of the tumors responding. We have a platform to build on and we can also explain why it’s working,” he concluded.

Dordaviprone is now undergoing further trials and has achieved FDA Fast Track Designation for the treatment of adult recurrent H3 K27M-mutant high-grade glioma, Rare Pediatric Disease Designation for treatment of H3 K27M-mutant glioma, and Orphan Drug Designations for the treatment of glioblastoma and for the treatment of malignant glioma.

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