P1, N=102, Recruiting, Jazz Pharmaceuticals | Trial primary completion date: Dec 2025 --> Jul 2026

P2, N=90, Not yet recruiting, Jazz Pharmaceuticals

Treatment was well tolerated, with only grade 1-2 adverse events reported. Larger randomized studies are needed to validate efficacy and long-term safety.

P1, N=20, Completed, University of Nebraska | Active, not recruiting --> Completed | Trial completion date: Aug 2027 --> Mar 2025 | Trial primary completion date: Oct 2026 --> Mar 2025

Dordaviprone (ONC201) and its chemical derivative with nanomolar potency, ONC206, induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). We also saw that ONC206 very significantly prolonged survival of medulloblastoma-bearing mice, both in genetically engineered mouse models and patient-derived xenografts. Our study provides a strong rationale for testing the efficacy of ONC206 in the treatment of patients with medulloblastoma and has set the stage for a clinical trial with this agent in pediatric patients with recurrent malignant brain tumors, including medulloblastoma ( NCT04732065 ).

Inhibiting IDH mutations with vorasidenib lowers D-2HG and is beneficial to patients. Other drugs like ONC201 and metformin can metabolically suppress oncogenic chromatin states in pediatric gliomas. This dynamic cross talk between metabolism and epigenetics not only underpins tumor biology but also presents opportunities for innovative therapeutic strategies.

This work offers a biologically-informed, clinically translatable strategy integrating small molecule therapeutics with CAR T cell therapy and support the development of multi-agent immunotherapy trials for children with DIPG and other high-grade brain and spinal cord tumors. B7-H3 CAR T cells are cytotoxic against preclinical DMG models.ONC206 causes metabolic apoptosis in preclinical DMG models.B7-H3 CAR T cells and ONC206 have combinatorial efficacy against DMG.

P1, N=36, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | N=24 --> 36

Despite its minimal renal clearance, dordaviprone geometric mean AUC was increased by ~50% in severe RI participants, suggesting CYP3A4 activity may have been suppressed in these participants. The results of this study will be used to inform dordaviprone dosing in patients with RI.

P2, N=73, Terminated, Chimerix | Active, not recruiting --> Terminated; The Sponsor terminated the study to prioritize enrollment in a randomized Phase 3 trial of ONC201 in an earlier setting. This decision was unrelated to any safety concerns with dordaviprone (ONC201).

P2, N=360, Recruiting, University of California, San Francisco | Trial primary completion date: Dec 2025 --> Dec 2027

The ability of ONC201 to overcome cisplatin resistance and its synergistic antitumor effects highlight its promise as a candidate for combination therapy. These findings support the translational potential of targeting the ATF3/ATF4/CHOP axis to improve outcomes in patients with cisplatin resistant HNSCC.