P2, N=0, Withdrawn, University of Nebraska | N=27 --> 0 | Suspended --> Withdrawn | Trial primary completion date: Apr 2026 --> Apr 2027

P1, N=58, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Jul 2026 --> Jul 2028 | Trial primary completion date: Feb 2026 --> Feb 2028

We propose that concurrent treatment with ONC201 may delay onset of resistance to RAS inhibitor therapy. ClpP activation by dordaviprone/ONC201 suppressed PDAC cell growth and overcame resistance to the RAS(ON) multi-selective inhibitor RMC-7977, providing support for investigating this combination as a potential combination treatment for KRAS-mutant pancreatic cancer.

P1, N=36, Recruiting, National Cancer Institute (NCI) | Trial primary completion date: Mar 2026 --> May 2027

Moreover, the chemical drug ONC201 was shown to effectively impede ESCC progression induced by the hyperactive IRF2BPL-IGFBP2 axis in tumor cells. Collectively, our findings verified that the IRF2BPL-IGFBP2 axis plays a critical role in enhancing ESCC progression by increasing the malignancy of ESCC cells and fostering an immune-deficient tumor microenvironment. Targeting the IRF2BPL-IGFBP2 axis may represent a promising therapeutic strategy for ESCC.

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.