ONC201 dordaviprone

Overview of ONC201 in H3 K27M Glioma

ONC201, also called dordaviprone, is a first-in-class small molecule imipridone that selectively binds to the G-protein coupled dopamine receptor D2 (DRD2) and the mitochondrial protease ClpP. Orally administered ONC201 appears to be well tolerated and active in some patients with specific forms of advanced cancer.

The registration program for ONC201 focuses on patients with brain tumors that contain the H3 K27M mutation based on durable objective responses in the recurrent setting. The ACTION study is a randomized, double-blind, placebo-controlled Phase 3 clinical trial evaluating ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma following radiotherapy.

For clinical trial options
please visit

What is the H3 K27M mutation?

H3 K27M refers to a specific mutation in one of the genes that encode for proteins called histone H3. This mutation is almost exclusively found in brain tumors called glioma, which means the tumor has arisen from glial cells normally present in the central nervous system. Gliomas that contain the H3 K27M mutation undergo a specific change in histone H3 proteins that prevents methylation at a specific site, and results in H3 K27M trimethyl loss (H3 K27me3-loss) that alters the expression of many genes.  This is thought to be a molecular driver of the disease and is commonly associated with a less favorable diagnosis relative to gliomas that do not harbor this mutation.. The H3 K27M can also be called H3 K28M or H3 K27-altered (H3 is sometimes referred to as histone H3, H3F3A, HIST1H3B, HIST1H3C, H3.3 or H3.1).

The H3 K27M mutation is found in the majority of diffuse midline gliomas (DMGs), which includes tumors located in central regions of the central nervous system such as the brainstem and thalamus. Prior to molecular-based classifications for diagnosis that began in 2016, DMGs were often referred to by their specific location within the central nervous system. For example, brainstem gliomas located in the pons were historically referred to as diffuse intrinsic pontine glioma (DIPG), and this terminology is occasionally still used.

H3 K27M-mutant DMG is a World Health Organization (WHO) Grade IV brain tumor. Radiation remains the sole standard-of-care intervention thought to provide transient benefit. Disease relapse is virtually inevitable, and no systemic therapy has proven effective for this disease.

While H3 K27M can be found in tumor locations throughout the central nervous system and across age groups, the mutation has a higher incidence in midline locations and in relatively young patients. The H3 K27M mutation is occasionally found in cortical locations outside of the midline structures of the brain. The mutation can occur in several different types of brain tumors, including tumors that were traditionally called glioblastoma (GBM), high grade glioma, diffuse midline glioma, or diffuse intrinsic pontine glioma (DIPG) based on their location or histology.

Testing for the H3 K27M mutation is often reflexively performed for diffuse midline glioma at diagnosis via methods that include immunohistochemistry (IHC) staining and gene sequencing.

ONC201 in Patients with H3 K27M-mutant Glioma

In November 2021, an integrated safety and efficacy analysis of ONC201 monotherapy for the treatment of recurrent H3 K27M-mutant diffuse midline glioma was reported at the Society for Neuro-Oncology (SNO) annual meeting. Dual-reader, blinded independent central review (BICR) by Response Assessment in Neuro-Oncology – High Grade Glioma (RANO-HGG) criteria determined the overall response rate (ORR) was 20% (95%CI, 10.0–33.7). Median time to response was 8.3 months (range, 1.9–15.9), followed by an 11.2 month median duration of response (95%CI, 3.8–not reached).   The disease control rate was 40% and 6- and 12-month progression free survival (PFS) were 35% and 30%, respectively. In addition, ORR by BICR using either RANO-HGG or RANO Low Grade Glioma (RANO-LGG) criteria was 30% (95%CI, 17.9–44.6) and the disease control rate was 42%.

ONC201 appears to be well tolerated in clinical studies of patients with advanced cancer when administered at dose frequencies up to twice weekly. Based on clinical trials, the most common adverse events that occurred after treatment (treatment-emergent adverse events) were mild-to-moderate fatigue, nausea, and headache. The most common treatment-emergent adverse event that was considered related to ONC201 was fatigue. More severe adverse events (Grade >3) occurred in <10% of patients, and the majority of these events were considered not related to ONC201.

The Phase 3 ACTION clinical trial is currently enrolling. ACTION is a randomized, double-blind, placebo-controlled trial in patients with newly diagnosed diffuse glioma whose tumor harbors the H3 K27M-mutation. The primary endpoint of the study is overall survival (OS), with additional alpha allocation to progression-free survival (PFS). The study is enrolling in North America, Europe and Asia-Pacific.  For more information on this trial please click here.

ONC201 in Patients with Other Advanced Cancers

While the registration program for ONC201 is focused on H3 K27M-mutant glioma, preclinical studies have demonstrated its therapeutic potential for several other forms of advanced cancer. Additional indications for ONC201 are being evaluated in clinical studies where it may hold therapeutic promise as a monotherapy or in combination with other anti-cancer agents. For example, a Phase 2 investigator-initiated trial has identified objective responses to ONC201 monotherapy in specific types of neuroendocrine cancer called paraganglioma and pheochromocytoma (PC/PG) that has been shown to be sensitive to ONC201 in preclinical studies.