The drug is administered orally once weekly and is well tolerated. Dordaviprone offers a new targeted systemic therapy for DMG with proven safety, good tolerability, and meaningful clinical benefit.

The recent ONC201 FDA approval, however, suggests DIPG therapy is tractable...A proof-of-concept in vivo mouse xenograft experiment demonstrated a reduction in tumor volume beyond antibody treatment alone. The work here represents an important milestone in preclinical development of a novel deruxtecan-based ADC agent for an intractable pediatric brain cancer, concurrent with other ADC agents demonstrating real-world clinical efficacy and gaining approvals in multiple disease indications.

These studies implicate mitochondrial biogenesis as a biomarker of imipridone resistance and a focus for the development of combinatorial strategies to provide effective therapeutic options for a challenging pediatric brain tumor.

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

P2, N=30, Not yet recruiting, Jazz Pharmaceuticals

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.

P2, N=90, Recruiting, Jazz Pharmaceuticals | Not yet recruiting --> Recruiting

P1, N=20, Not yet recruiting, Prinses Maxima Centrum voor Kinderoncologie B.V.

B7-H3 CAR T cells combined with ONC206 is a feasible and efficacious multi-agent approach against multiple DIPG models.

P2, N=0, Withdrawn, University of Nebraska | N=27 --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 Withdrawn | Trial primary completion date: Apr 2026 --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