P2, N=208, Recruiting, BioVie Inc. | Trial completion date: Jan 2026 --> Aug 2026 | Trial primary completion date: Nov 2025 --> Jun 2026

P2, N=0, Withdrawn, University of Nebraska | N=27 --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 Withdrawn | Trial primary completion date: Apr 2026 --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

FAM83A is crucial in the advancement and spread of LUSC, as it promotes EMT and inhibits apoptosis via the activation of the ERK pathway. These findings highlight its potential as a strategic molecular target for the treatment of LUSC.

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

Similarly, ERK1/2 inhibition by SCH772984 impairs WED-induced neutrophil differentiation and bactericidal activity, decreasing PU.1 and CEBPβ expression without affecting TLR2 levels. These findings position TLR2 as a key therapeutic target for neutropenia, with WED effectively promoting neutrophil differentiation via TLR2 and MEK/ERK pathway activation. This study highlights the therapeutic potential of targeting TLR2 to alleviate neutropenia and underscores the utility of a multi-omics approach in uncovering drug mechanisms.

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.

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.