Modeyso (dordaviprone)

Among these are histone deacetylase inhibitors (HDACis), receptor tyrosine kinase inhibitors, and novel agents such as ONC201 and unesbulin that target metabolic and epigenetic pathways respectively...Despite these advances, challenges such as drug delivery across the blood-brain barrier and therapeutic resistance persist, necessitating the development of combination therapies and innovative delivery methods. Ongoing research is focused on refining these strategies and exploring additional molecular and immunological targets to improve outcomes for children with DMG.

P3, N=510, Recruiting, Jazz Pharmaceuticals | Trial completion date: Aug 2026 --> Jun 2028 | Trial primary completion date: Aug 2026 --> Jun 2028

Ovarian cancer has a poor clinical prognosis due to chemoresistance following carboplatin/paclitaxel treatment...The therapeutic efficacy of these combinations was also proved in patient-derived tumor organoid models (PDTO), leading to their structural disintegration and reduced viability. Collectively, our study highlights that ABT-737, through BCL-xL inhibition and synergy with ER stress inducers, triggers ovarian cancer death, offering promising strategies for overcoming chemoresistance in relapsed ovarian cancer.

To overcome this issue, herein, we developed a cobalt-pheophytin (CoPheo) coordination micelle chelating two chemotherapeutic agents including ONC201 and Palbociclib (Pal), yielding CoPheo-ONC201-Pal-F127. In addition, ONC201-mediated mitogen-activated protein kinase kinase (MEK) inhibition, combined with Pal-induced CDK4/6 blockade, promotes cellular senescence and remodels the tumor microenvironment. These three independent mechanisms collectively establish a mutually enhanced therapeutic strategy capable of overcoming the complex drug resistance driven by multiple downstream signaling pathways in KRAS-mutant pancreatic cancer.

Our results highlight ONC206 as a novel therapeutic option for patients with high-risk medulloblastoma and provide strong rationale for testing the efficacy of ONC206 in the treatment of these patients.

The individualized regimen comprised trametinib and everolimus for dual pathway inhibition, the tissue-agnostic agent dordaviprone (ONC201), metabolic modulation with 2-deoxy-D-glucose, and electric field-based therapy. The systematic integration of comprehensive molecular profiling with mechanistically rational treatment selection may contribute to meaningful radiological and clinical benefit in this otherwise uniformly fatal disease. These observations support further investigation of individualized, pathway-targeted approaches in prospective studies and N-of-1 trial frameworks.

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.

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