Dr Bagley on the ACTION Trial of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas

Stephen Bagley, MD, MSCE, assistant professor of medicine, hematology-oncology, University of Pennsylvania Hospital, assistant professor of medicine, neurosurgery, Penn Medicine, discusses the evaluation of the small molecule ONC201 in the phase 3 ACTION trial (NCT05580562) for patients with H3K27M-mutant diffuse midline gliomas.

Diffuse midline gliomas are rare malignancies, with a higher incidence in pediatric populations, Bagley begins. This tumor type has historically been considered difficult to treat due to its location in the central nervous system, spanning from the spinal cord to the brain stem to the thalamus, Bagley explains.

The first-in-class imipridone ONC201 (dordaviprone) penetrates the blood-brain barrier to target the dopamine receptor D2/3 (DRD2) which in turn activates an integrated stress response, thereby triggering programmed cell death in cancer cells. DRD2 is hypothesized to be enriched in these brain structures, indicating that ONC201 may have a role in the treatment armamentarium as an effective antagonist. An integrated pooled analysis of 5 open-label, early-phase trials of ONC201 has demonstrated promising efficacy signals with the agent in patients with recurrent diffuse midline glioma. Orally administered ONC201 also exhibited radiographic responses in a subset of patients with recurrent disease, Bagley notes.

Based on these initial data, the large, international, randomized ACTION trial was initiated, Bagley says. The study will enroll patients with newly diagnosed H3K27M-mutant diffuse glioma who completed standard frontline radiotherapy. Patients will be randomly assigned 1:1:1 to receive either placebo, once-weekly ONC201, or twice-weekly ONC201 on 2 consecutive days.

The study’s primary efficacy end points are overall survival (OS) and progression-free survival (PFS), evaluated with response assessment in neuro-oncology-high grade glioma criteria by blinded independent central review. Other secondary objectives include safety, additional efficacy end points, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization.

The ongoing trial will assess the efficacy of ONC201 in a broader context and provide insight into its potential role in diffuse midline glioma, Bagley explains. As recruitment progresses, the oncology community anticipates that the results of this study will further inform the management of this challenging tumor, he says. The ACTION study is currently enrolling in the United States, with plans to open at other international sites.