JZP3507 / Jazz - LARVOL DELTA

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

A phase 2 study to investigate the efficacy and safety of JZP3507 (formerly ONC206) in adults with recurrent grade 2 or 3 meningioma (SNO 2026) - No abstract available

Clinical • P2 data • Brain Cancer • Meningioma • Solid Tumor

Allosteric ClpP agonist ONC206 alters mitochondrial metabolism to elicit anti-cancer efficacy in H3 G34-mutant glioma (SNO 2026) - No abstract available

Clinical • Brain Cancer • Glioma • Oncology • Solid Tumor

Enhancing CAR T cell efficacy in diffuse midline glioma through combinatorial strategies (EANO 2026) - P1 | "Imipridones, including ONC206, have emerged as promising agents in DMG, inducing mitochondrial dysfunction and activation of integrated stress response pathways that may sensitize tumor cells to immune-mediated killing... We demonstrate that imipridone-mediated tumor sensitization enhances CAR T cell efficacy without compromising T cell function. The combination improves mouse survival in multiple orthotopic DMG models. This strategy provides a clinically actionable framework to overcome resistance and improve outcomes in this lethal disease."

CAR T-Cell Therapy • Clinical • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Oral Cancer • Solid Tumor • ATF4 • CASP3 • CASP7 • DRD2 • GZMB • IFNG • IFNL1 • TNFA

A Study of JZP3507 (ONC206) in Recurrent Grade 2 or 3 Meningioma (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Jazz Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • Meningioma • Oncology • Solid Tumor

Pilot multimodal immune profiling of ONC206 ± radiotherapy in an immunocompetent H3.3K27M diffuse midline glioma model (ISPNO 2026) - "ONC206 – a potent imipridone analog of FDA-approved ONC201 – is currently being evaluated in clinical trials for DMG patients with minimal reported toxicity and potential immunomodulatory activity. These preliminary findings support the feasibility of paired brain–blood immune profiling in DMG and suggest ONC206+RT may enhance immune recruitment while triggering counter-regulatory checkpoint programs in T cells. Ongoing cohort expansion integrated with spatial readouts will prioritize mechanisms and candidate biomarkers for validation and rational combination design."

IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor • CD4 • CD69 • CD8 • CTLA4 • PD-1

Dordaviprone (ONC201) treatment generates canonical and non-canonical antigens that can be exploited for immunotherapy targets in diffuse midline glioma (ISPNO 2026) - "However, the identity and immunogenic relevance of drug-induced DMG antigens remain undefined.Here, we employed immunopeptidomics to characterise the human leukocyte antigen class I (HLA-I)–bound peptide repertoire following treatment of DMG cells with ONC201 and the related imipridones ONC206 and TR107...In summary, dordaviprone and related imipridones reprogram the DMG antigen landscape by expanding both canonical and non-canonical tumour peptides. These findings establish a mechanistic and translational framework for exploiting drug-induced antigen presentation to enable personalised immunotherapy for DMG."

IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor • SDHA

The Imipridone ONC206 Inhibits Tumor Growth and Improves Survival in Patient-Derived Xenograft Models of Uveal Melanoma. (PubMed, Cancers (Basel)) - " Our findings position ONC206 as a mechanistically distinct agent to target mitochondrial metabolism and to inhibit mUM. As ONC206 is currently being evaluated in multiple clinical studies, our data support further evaluation as a potential new therapeutic strategy for mUM."

Journal • Preclinical • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Integrated Phenotypic and Transcriptomic Profiling Positions ONC212 as a Lead Imipridone in Androgen-Independent Prostate Cancer Models. (PubMed, Int J Mol Sci) - "DU145 and PC3 AIPC cells were treated with ONC201 (parent compound), ONC206, or ONC212...Imipridones induced a time-dependent cell-cycle redistribution with increased sub-G1 accumulation and modulated mitochondrial membrane potential and mass in a context-dependent manner. Collectively, these findings position ONC212 as a leading imipridone candidate in AIPC models, combining potent inhibition of tumor and stem-like cell functions with a coherent stress-response signature that supports further translational evaluation."

Journal • Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ATF4

Single-nucleus profiling of postmortem diffuse midline gliomas identifies mitochondrial biogenesis as a resistance mechanism to imipridone therapy. (PubMed, Neuro Oncol) - "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."

Journal • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • PPARGC1A

ClpP Activation in High-Risk Medulloblastoma: ONC206 as a Potent Inducer of the Integrated Stress Response and Mitochondrial Damage for a Broader Therapeutic Window. (PubMed, Neuro Oncol) - No abstract available

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor

Imipridones ONC201, ONC206, and ONC212 show potent killing and colony arrest of small-cell lung cancer cell lines (AACR 2026) - "The present findings suggest that SCLC may be highly sensitive to imipridones, particularly ONC212. Future works will aim to explore combination therapies and potential mechanisms including senescence induction, cell cycle alterations that may lead to reproductive arrest, metabolic changes, and alterations in growth and survival pathways in order to further characterize sensitivity and the colony arrest phenotype."

Preclinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ATF4

Determining mechanisms of ONC212-resistance in uveal melanoma to develop combination therapy strategies (AACR 2026) - "ONC212-resistant clones exhibited higher IC50, and RI compared to parental cells and showed cross-resistance to other imipridones (ONC201, ONC206), suggesting shared mechanisms of resistance...Importantly, ONC201, the first imipridone was recently approved for therapy of midline gliomas. Therefore, lessons learned from this study may benefit patients acquiring resistance to ONC201 in future as well."

Combination therapy • Brain Cancer • Eye Cancer • Glioma • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Imipridone treatment activates canonical NFkB and inflammatory signaling in THP1 differentiated macrophages (IMMUNOLOGY 2026) - "Following differentiation, we treated the cells with 5µM or 2µM ONC201, 1.5µM or 0.75µM ONC206, or 0.1µM or 0.05µM ONC212 and collected lysates for western blot. Using the hallmarks gene set, we found that increased expression of genes associated with a baseline inflammatory, IFNα and IFNγ response were associated with patient radiographic response... We have identified a link between a more immunologically active TME and response to ONC201 in patients with DMG, and that changes in NFkB signaling occurred following imipridone treatment of the THP1 cell line. We will continue our analysis of changes in cytokine production through ELISA and luciferase reporter assays."

Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • High Grade Glioma • Solid Tumor • ATF4 • GLI2 • IFNA1 • IFNG • IL1B • NLRP3

Allosteric ClpP agonist ONC206 alters mitochondrial metabolism, stress response, chromatin accessibility and cell cycle to elicit apoptosis in pheochromocytoma (AACR 2025) - "ONC206 also demonstrated superior cell viability inhibition and apoptosis induction in PC cell lines relative to temozolomide and sunitinib at equivalent concentrations. Accordingly, western blot showed ONC206 downregulated mitochondrial proteins (ClpX, SDHB), neuroendocrine markers (tyrosine hydroxylase, enolase-2, synaptophysin) and upregulated stress response (ATF4) in hPheo1 cells. Thus, ONC206 is a potent novel agent that is superior to SOC and dordaviprone that have shown clinical activity in PC-PG."

Oncology • Solid Tumor • ANXA5 • ATF4 • DRD2 • SDHB • SYP

Preclinical combination of ONC206 with radiotherapy and temozolomide in a GBM mouse orthotopic model (AACR 2024) - P1 | "We previously reported that the first-in-class imipridone small-molecule Dordaviprone (ONC201) decreases protein chaperone ClpX to unleash mitochondrial protease ClpP activity, integrated stress response and cell death. There are two ongoing clinical trials with ONC206: single weekly or multiple-day weekly dose regimens of single-agent, oral ONC206 in patients with recurrent, primary central nervous system (CNS) neoplasms (NCT04541082) and ONC206 alone or in combination with radiation therapy in treating patients with diffuse midline gliomas that is newly diagnosed or has come back (recurrent) or other recurrent primary malignant CNS tumors (NCT04732065). Future studies evaluating the role of immune function, mitochondrial metabolism, dopamine receptors, the ISR and TRAIL pathway in the synergistic effect would support further development of the triple combination regimen of ONC206, TMZ and radiation therapy for GBM clinical trial."

Preclinical • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor

Reduced severity of radiation esophagitis in mice following 2 weeks of ONC212 treatment [WITHDRAWN] (AACR 2025) - "Our results provide a strategy with an orally bioavailable drug for treatment of severe esophagitis that is caused by therapeutic radiotherapy involving the esophagus. Additional directions for future research include studies of other TRAIL pathway agonists such as TRAIL itself, TLY012, or other imipridones including ONC201 or ONC206 effects on severity of radiation esophagitis."

Preclinical • Breast Cancer • Esophageal Cancer • Head and Neck Cancer • Lung Cancer • Oncology • Solid Tumor • CCL2 • CCL22 • CCL3 • CXCL12 • EGF • IGF1 • IL16

Preclinical analysis of ONC206 and ONC212 with lurbinectedin in pancreatic cancer (AACR 2025) - "Our group recently described lurbinectedin's potency as both a single agent and combinatorial agent with irinotecan and 5-fluorouracil in pancreatic cancer cell lines...Future studies will analyze whether a combination of lurbinectedin and ONC212 or lurbinectedin and ONC206, another imipridone and chemical analogue of ONC201, proves more efficient at killing pancreatic tumor cells in vitro. Our results are developing insights into novel combinatorial therapeutic regimens while investigating the molecular mechanisms underlying synergism."

Preclinical • Lung Cancer • Oncology • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor

Imipridones ONC201, ONC206, and ONC212 promote immune-mediated cell death and anti-tumor activity in biliary tract cancer models in vitro (AACR 2025) - "Imipridones and MEK inhibitors exhibit potent antineoplastic effects in BTC cell lines. In RBE cells, half maximal inhibitory concentrations (IC50) were 2.53 μM (ONC201), 917 nM (ONC206), 46.99 nM (ONC212), and 5.94 μM (trametinib), while in HuCCT1 cells, they were 1.97 μM (ONC201), 1.06 μM (ONC206), 38.95 nM (ONC212), and 3.71 μM (trametinib). Imipridones (ONC201 and ONC212) with trametinib showed synergy in HuCCT1 cells."

Preclinical • Biliary Cancer • Biliary Tract Cancer • Oncology • Solid Tumor • DRD2

Impact of hypoxia on the integrated stress response activated by imipridones ONC201 and ONC206 in pediatric diffuse midline glioma cells (AACR 2024) - P=N/A, P1 | "Imipridones mediate apoptosis through the upregulation of the TRAIL death receptor DR5 and the activation of the integrated stress response (ISR), so western blots were used to show changes in the ISR protein expression in ONC201 treated DMG cells at multiple different degrees of hypoxia. To understand how hypoxia inducible factors (HIFs) play a role in resistance and susceptibility to ONC201 or ONC206, HIF-1a, HIF-2a, and HIF-3a were knocked down showing altered ISR protein expression after treating with the imipridones under hypoxic and normoxic conditions."

Clinical • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • High Grade Glioma • Oncology • Solid Tumor • EPAS1 • HIF1A

The anti-tumor efficacy and immune effects of combining of ceralasertib, an oral ATR kinase inhibitor, with imipridones, in prostate cancer treatment in vitro and in vivo (AACR 2024) - "Thus, we combined ceralasertib with imipridones (ONC201 and ONC206), which target mitochondrial caseinolytic protease P (ClpP) and the integrated stress response, resulting in enhanced antitumor efficacy in vitro...Preliminary results include cytokine profiling using the Luminex 200 technology to understand treatment induced changes in the tumor microenvironment (TME) from both in vitro and in vivo studies. Our results guide novel clinical trials for effective clinical responses in mCPRC patients."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Pre-clinical efficacy of tumor treating fields and imipridones in glioblastoma and colorectal cancer cell lines (AACR 2025) - "We then treated cells with imipridones at the identified IC50 doses either alone or together with 200kHz TTFields and collected cell lysate after 72 hours.We found differences in AKT phosphorylation across our treatment conditions (control, ONC201, ONC206, ONC212, TTF, TTF + ONC201, TTF + ONC206, and TTF + ONC212). These findings are significant in guiding future in vivo experiments and offering insight on whether TTField and imipridone treatment can be further explored in clinical trials."

Preclinical • Brain Cancer • CNS Tumor • Colorectal Cancer • Glioblastoma • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Study of JZP3507 (ONC206) in Recurrent Grade 2 or 3 Meningioma (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Jazz Pharmaceuticals

New P2 trial • Brain Cancer • Meningioma • Oncology • Solid Tumor

ONC206 inhibits tumour growth and is a potential novel therapeutic strategy for refractory medulloblastoma (AACR 2024) - "Dordaviprone (ONC201) and its chemical derivative with nanomolar potency ONC206 are inhibitors of the dopamine receptor 2 (DRD2) and more importantly induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP)...Mice from both Group 3 PDXs also responded to ONC206, with 25% of ONC206 treated animals exhibiting long-term tumor-free survival. Our results highlight ONC206 as a novel attractive therapeutic option for patients with relapsed medulloblastoma and importantly pave the way for a clinical trial testing the efficacy of ONC206 in the treatment of these patients."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Medulloblastoma • Oncology • Solid Tumor • ATF4 • CLPP • DRD2

Imipridones (ONC201, ONC206 and ONC212) modulate MGMT and ClpX expression in DIPG cell lines (AACR 2025) - "Temozolomide (TMZ) is an oral alkylating agent that is generally well tolerated. We are going to test this mechanism of synergy and therapeutic efficacy in vivo by treating orthotopic DIPG mouse models with imipridones -/+ TMZ. Our results support further studies combining imipridones (ONC201, ONC206 and ONC212) with TMZ and RT as a reasonable and safe therapeutic option for DIPG."

Preclinical • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor • MGMT