Modeyso (dordaviprone) / Jazz - LARVOL DELTA

Differential Redox Capacity In Pediatric and Adult High-Grade Gliomas Reveals Therapeutic Vulnerabilities (ASTRO 2026) - "As a result, radiotherapy (RT) ± ONC201 remains the standard treatment, though it is not curative... Given DIPG's distinct biology relative to GBM, antioxidant metabolism dysregulation warrants exploration. Altogether, the increased sensitivity of DIPG cells to AUR (versus GBM) identifies TR as a key therapeutic target with direct implications for radiosensitivity. These findings support further investigation of AUR and other inhibitors of the thioredoxin antioxidant system as a strategy to overwhelm the redox buffering capacity of DIPG cells and improve long-term tumor response to RT."

Clinical • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor • CAT

Patterns of Failure in Primary Spinal Gliomas: Impact of H3K27M Mutation Status after Radiotherapy (ASTRO 2026) - "We evaluated a cohort of patients with primary spinal gliomas for clinical outcomes and patterns of failure after receipt of definitive radiotherapy (45-60 Gy), with or without temozolomide. H3K27M-mutant spinal gliomas demonstrated higher rates of disseminated failure (60.0% vs 38.5%), suggesting distinct biological behavior requiring enhanced neuraxis surveillance and intensification of therapy. While median OS of 7.7 years for WHO Grade 1-2 tumors was favorable, outcomes for Grade 3-4 tumors (16.2 months) remained poor. These findings support routine molecular profiling including H3K27M testing to guide prognosis, surveillance strategies, and eligibility for emerging targeted therapies such as ONC201 for H3K27M-mutant tumors."

Brain Cancer • Glioma • Oncology • Solid Tumor

Phase I trial of a novel first-in-class drug ONC201 as a post-transplant maintenance for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (ASH 2025) - P1 | "GVHD prophylaxis included tacrolimus and methotrexate with or withoutantithymocyte globulin. ONC201 was well tolerated with no observed DLT and a manageable safety profile. The AEprofile was not different from AEs expected in a post-transplant population. Rates of cytopeniaswere low."

Clinical • P1 data • Post-transplantation • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Leukemia • Liver Failure • Myelodysplastic Syndrome • Neutropenia • Thrombocytopenia • Transplantation • ASXL1 • BCOR • DRD2 • STAG2 • TP53 • U2AF1

Dordaviprone Maintenance After Allogeneic HCT for High-Risk Acute Myeloid Leukemia and Myelodysplastic Neoplasm. (PubMed, Am J Hematol) - P1 | "Posttransplant dordaviprone maintenance was determined to be safe with low rates of cytopenias and promising efficacy in this high-risk population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03932643."

Journal • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia • Transplantation

In vitro and in vivo evaluation of CT-179 in combination with ONC201 and ONC206 in patient-derived models of diffuse midline glioma (SNO 2026) - No abstract available

Combination therapy • Preclinical • Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor

Marked functional and radiographic response to dordaviprone in an H3 K27-altered diffuse midline glioma of the medulla (SNO 2026) - No abstract available

Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor

Modeyso: Newly added patent in Orange Book (Orange Book) - Expiry on Aug 30, 2032

Patent • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

An ancillary study of the BIOMEDE trial using patient-derived cellular models to predict therapeutic response and disease dissemination in diffuse midline glioma (EANO 2026) - "Drug sensitivity was evaluated using viability-based assays across a panel of clinically relevant compounds including everolimus, ONC201/206, afatinib, trametinib and niraparib. This ancillary study establishes a comprehensive functional platform based on BIOMEDE-derived patient models, with the aim of enhancing and refining the biological and clinical insights generated by the trial. Ongoing molecular analyses will further characterize transcriptional programs underlying these functional phenotypes and support integrated analyses combining functional, molecular, and clinical data."

Clinical • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

The FOXO3a-MXI1-c-Myc Axis Defines a Metabolic Vulnerability in Pediatric H3K27M-Altered Diffuse Midline Glioma (EANO 2026) - "Functional studies were performed in SF8628 DMG cells using CRISPR/Cas9 FOXO3a knockout (KO), RNA sequencing, ATP measurements, and ONC201 sensitivity assays... Constitutive FOXO3a inactivation coupled with MXI1 loss reinforces c-Myc-driven metabolic reprogramming and promotes therapeutic escape in H3K27M-mutant DMGs. Restoring the FOXO3a-MXI1 regulatory checkpoint suppresses oncogenic metabolism and sensitizes tumors to imipridones. MXI1-mimetics or FOXO3a-activating compounds may represent promising next-generation therapeutics to overcome metabolic resilience and improve clinical outcomes in DMGs."

Clinical • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • FOXO3 • MXI1 • MYC

A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma. (PubMed, Oncologist) - P2 | "ONC201 monotherapy did not induce objective responses in recurrent or refractory metastatic breast or endometrial cancer at the RP2D dose of 625 mg weekly but had an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03394027)."

Journal • Metastases • P2 data • Breast Cancer • Endometrial Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma. (PubMed, Neuro Oncol) - P1 | "Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response."

Circulating tumor DNA • Journal • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

Mitochondrial CLPP in Health and Disease: Mechanisms, Therapeutic Duality and Emerging Opportunities. (PubMed, J Inherit Metab Dis) - "Pharmacological CLPP hyperactivation drives broad degradation of mitochondrial proteins and can selectively collapse mitochondrial fitness in susceptible tumor cells, an approach now clinically validated by the approval of dordaviprone for mutant diffuse midline glioma...In this review, we discuss the physiological functions and substrate selectivity of CLPXP, the mechanistic basis and clinical development of CLPP inhibitors and activators, and the growing evidence that therapeutic responses depend strongly on tissue identity, metabolic state and the nature of the underlying mitochondrial defect. Together, these findings position CLPP as a context-dependent therapeutic switch whose activity may need to be tuned in opposite directions to either preserve mitochondrial resilience or selectively dismantle mitochondrial fitness."

Journal • Review • Brain Cancer • CNS Disorders • Diffuse Midline Glioma • Glioma • Metabolic Disorders • Oncology • Reperfusion Injury • Solid Tumor

Diffuse Intrinsic Pontine Glioma in the Era of H3 K27-Altered Diffuse Midline Glioma. (PubMed, Crit Rev Oncol Hematol) - "We also examine dordaviprone, the first systemic therapy to receive FDA accelerated approval for H3 K27M-mutant DMG with progressive disease following prior therapy, while emphasizing that the regulatory efficacy population excluded DIPG and therefore does not establish efficacy in classic pediatric pontine disease. Trial design must also explicitly separate anatomic phenotype from molecular taxonomy. Priorities include molecularly stratified enrollment, pharmacokinetically verified brainstem exposure, rational combinations, and endpoints integrating survival, neurologic function, and quality of life."

Journal • Review • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • ACVR1 • PDGFRA • PPM1D • TP53

ONC201 in Treating Patients With Relapsed or Refractory Acute Leukemia or High-Risk Myelodysplastic Syndrome (clinicaltrials.gov) - P1/2 | N=58 | Terminated | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Nov 2026 ➔ Aug 2026 | Active, not recruiting ➔ Terminated | Trial primary completion date: Nov 2026 ➔ Aug 2026; <75% participants

Trial completion date • Trial primary completion date • Trial termination • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • T Acute Lymphoblastic Leukemia

Leveraging the immunomodulatory effects of dordaviprone to induce adaptive immune surveillance in diffuse midline glioma (SNO 2026) - No abstract available

Immunomodulating • Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor

Neuroinflammation in Central Nervous System Tumors. (PubMed, Cells) - "The inflammatory profiles of IDH-wildtype and IDH-mutant gliomas and of secondary brain metastases are contrasted. Finally, the correlates of functional neuroimaging, liquid biopsies, and resistance mechanisms to conventional therapies are analyzed, including the GIANT and SENIPERA clinical trials, CARv3-TEAM-E bivalent cellular immunotherapy preconditioned with the LDC + R regimen, and the accelerated approval of dordaviprone (Modeyso) in H3 K27M-mutant diffuse midline gliomas."

IO biomarker • Journal • Review • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor

ONC201/dordaviprone for H3 K27M-mutant tumors: Discovery, mechanisms, therapeutic potential, and future directions. (PubMed, Genes Dis) - "Despite these advances, emerging resistance mechanisms, including ClpP mutations and adaptive activation of the EGFR and MAPK/AKT pathways, highlight the need for biomarker development and rational combination strategies. Together, these insights position ONC201 as both a therapeutic milestone and a platform for future translational oncology innovation."

Journal • Review • Brain Cancer • Diffuse Midline Glioma • Glioma • Gynecologic Cancers • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • DRD2

Dordaviprone treatment in an AYA patient with primary spinal H3K27M-altered diffuse midline glioma (SNO 2026) - No abstract available

Clinical • Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor

Dordaviprone (ONC201) in a pediatric patient with recurrent H3 K27M-mutant diffuse glioma and leptomeningeal disease (EANO 2026) - P | "Patients with LMD were excluded from prior response analyses due to challenges with radiographic evaluation by standard response criteria.Material and ONC028 (NCT04617002) was a US-based expanded access protocol to provide dordaviprone access to patients ineligible for clinical trials, including patients with LMD. An 11-year-old female patient with progressive right thalamic H3 K27M-mutant DMG and extensive LMD, previously treated with craniospinal irradiation (36 Gy with 18-Gy focal boost to right thalamic lesion), concurrent and adjuvant temozolomide, dabrafenib and trametinib, and a single dose of bevacizumab, was enrolled in ONC028. This case report suggests a potential role for dordaviprone use in recurrent H3 K27M-mutant DMG with LMD."

Clinical • Brain Cancer • Diffuse Glioma • Diffuse Midline Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor

Window-of-opportunity study of ONC201 in pediatric patients with diffuse intrinsic pontine glioma (DIPG) and thalamic glioma. (ASCO 2022) - P1 | "Arm H has a planned enrollment of 27 patients. Each patient will undergo biopsy at a single prespecified biopsy window, which will be assigned at enrollment (Table); plasma for PK analysis will be collected from all patients at all time points shown in the Table, with additional collection pre-dose and 0.5 h post first dose."

Clinical • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • DRD2

Pharmacological inhibition of CD147 restrains tumor progression and remodels tumor-stroma crosstalk in H3K27-altered diffuse midline glioma (EANO 2026) - "Combination with ONC201 produced synergistic viability reduction... Overall, these findings identify BSG/CD147 as a key regulator of tumor growth and microenvironment architecture in DMG, supporting its inhibition as a promising therapeutic strategy."

Stroma • Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Oncology • Solid Tumor • BSG • CASP3 • CASP9 • CD133 • CD163 • CD68 • CDKN1A • SOX2

Dordaviprone AE Management and Workflow Optimization: Team-Based Implementation (SNO 2026) - "Supported by This activity is supported by an educational grant from Jazz Pharmaceuticals, Inc."

Effects of reactive oxygen species on histone variants and ONC-201 response in H3K27M diffuse midline gliomas (SNO 2026) - No abstract available

Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor

THX6 as a Potent Mitochondrial Protease hClpP Activator for Pediatric Diffuse Midline Glioma Treatment (EANO 2026) - "THX6 is a novel candidate drug with superior target engagement and higher cytotoxicity in DIPG models compared to the current gold standard, ONC201. Predicted to cross the blood-brain barrier, THX6 represents a promising lead for the ongoing in vivo pre-clinical investigation in DMG, also using pharmacokinetic and pharmacodynamic parameters determined by surface plasmon resonance building a sensor-chip that immobilizes hClpP, and using THX6 as a ligand."

Clinical • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • High Grade Glioma • Medulloblastoma • Oncology • Solid Tumor

Clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas is driven by disruption of integrated metabolic and epigenetic pathways. (PubMed, Cancer Discov) - "This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuro-glial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction."

Journal • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor