dordaviprone (ONC201)

P2, N=324, Recruiting, University of California, San Francisco | Active, not recruiting --> Recruiting | N=143 --> 324

Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate the effect of GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

P1, N=27, Not yet recruiting, University of Nebraska | Trial completion date: Jan 2027 --> Apr 2027 | Initiation date: Jan 2024 --> Apr 2024 | Trial primary completion date: Jan 2026 --> Apr 2026

H3K27M-mutant diffuse gliomas occasionally occur in nonmidline cerebrum. ONC201 exhibits activity in H3K27M-mutant gliomas irrespective of CNS location.

In this study, for the first time, piezoelectrically catalyzed Mg -doped hydroxyapatite (Mg-HAP) nanoparticles, which are coated with a mesoporous silica layer and loaded with ONC201 as an agonist to specifically target the death receptor DR5 on tumor cells, ultimately developing an Mg-HAP@MS/ONC201 nanoparticle (MHMO NP) system, are engineered...In summary, a dual-targeting therapy system that targets both tumor cells and the tumor microenvironment under piezoelectric catalysis is designed. This system holds substantial potential for advancements in tumor immunotherapy.

Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease.The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR).Here we demonstrate that the novel imipridone analog, TR-57, has efficacy as a single agent and synergises with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Changes in protein expression suggest TR-57 activates the UPR, inhibits the AKT and ERK1/2 pathways and induces pro-apoptotic changes in the expression of proteins of the BCL-2 family.The study suggests that TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL.

P2, N=19, Terminated, Fox Chase Cancer Center | N=36 --> 19 | Suspended --> Terminated; Slow accrual

Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

ONC201, ONC206, and ONC212 are imipridones showing pro-apoptotic anti-cancer response...Additionally, pediatric solid tumor cells were treated with single-agent therapy with histone deacetylase inhibitors (HDACi) vorinostat, entinostat, and panobinostat, showing cell killing with all 3 HDACi drugs, with panobinostat showing the greatest potency...Our results introduce a novel class of small molecules to treat pediatric solid tumors in a precision medicine framework. Use of impridones in pediatric oncology is novel and shows promising pre-clinical efficacy in pediatric solid tumors, including in combination with HDAC inhibitors.

P1, N=20, Active, not recruiting, University of Nebraska

We provide specific detail of recent efforts to monitor CSF and plasma H3K27M cell-free DNA in patients undergoing therapy with the imipridone ONC201. Lastly, we discuss the future of therapeutic monitoring of H3K27M-DMG, including biomarkers such as mitochondrial DNA, mutant and modified histones, and novel sequencing-based approaches for improved detection methods.

Our studies reveal a therapeutic vulnerability of DIPG cells through targeting the SUV39H1-H3K9me3 pathway and compensatory signaling loops for treating this devastating disease. Combining SUV39H1-targeting chaetocin with other agents such as ONC201 may offer a new strategy for effective DIPG treatment.

P3, N=450, Recruiting, Chimerix

P2, N=0, Withdrawn, Masonic Cancer Center, University of Minnesota | N=36 --> 0 | Not yet recruiting --> Withdrawn

P2, N=143, Active, not recruiting, University of California, San Francisco | Recruiting --> Active, not recruiting | N=324 --> 143

P1, N=20, Active, not recruiting, University of Nebraska | Recruiting --> Active, not recruiting

Herein, we report on the combination study arm with ONC201, an orally available DRD2 and ClpP agonist, and paxalisib, a dual PI3K-mTOR inhibitor for patients who completed standard-of-care radiation (Cohort 2). The current median OS is encouraging compared to historical controls. At the meeting, we will present updated molecular characterization and early biological correlates in association with clinical outcomes including toxicity, OS, PK, and central imaging confirmed progression-free survival.

Overall, our data demonstrates the efficacy of ONC201 in H3K27M-mutant DMG and supports ONC201 as the first monotherapy to improve outcomes in patients with H3K27M-mutant DMG for whom few therapeutic options currently exist. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction.

The patient continuing to receive the combination at progression and following reirradiation also experienced a marked decrease in tumor size (MR axial diagnosis scan = 1248 mm2, current tumour area = 315 mm2, ~75% reduction), 10 months following radiological detection of progression. These data inform the phase II clinical trial (NCT05009992).

P1, N=24, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2025 --> Jan 2028 | Initiation date: May 2023 --> Mar 2024 | Trial primary completion date: Feb 2025 --> Jan 2026

P1, N=27, Suspended, University of Nebraska | Not yet recruiting --> Suspended

TIC10 can effectively inhibite the proliferation of leukemia cells and induce apoptosis, and have a certain intervention effect on AML induced by MLL-AF9, indicating that TIC10 as a potential candidate drug for the treatment of leukemia.

Transcriptomic analysis in everolimus resistant breast patient tumors and mitochondrial functional assays in resistant cell lines demonstrated increased mitochondrial respiration dependency, contributing to ONC201/TIC10 sensitivity. We propose that ONC201/TIC10 and modulation of mitochondrial function may provide an effective add-on therapy strategy for patients with metastatic ER+ BCs resistant to mTOR inhibitors.

Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023.

P1, N=27, Not yet recruiting, University of Nebraska

Here, we summarize dordaviprone's safety, interrogate its preclinical MOA- identifying the mitochondrial protease 'ClpP' as a biomarker of response, and discuss other ClpP-agonists, expanding the arsenal of potential weapons in the fight against DMG. Finally, we discuss combination strategies including ClpP-agonists, and its immunomodulatory effects suggestive of a role for the tumor microenvironment in DMG patients' response.

P1, N=20, Recruiting, University of Nebraska | Trial completion date: Jul 2025 --> Aug 2027 | Trial primary completion date: Jul 2023 --> Aug 2024

In conclusion, this study suggests that GsONC201 may improve OS in pediatric H3K27-altered pDMG patients without significant side effects. However, caution is warranted due to retrospective design and biases, highlighting the need for further randomized clinical studies to validate these findings.

P2, N=62, Recruiting, Ira Winer | Trial completion date: Apr 2024 --> Apr 2026 | Trial primary completion date: Apr 2023 --> Apr 2025

P2, N=95, Active, not recruiting, Chimerix | Trial primary completion date: Mar 2023 --> Jun 2023

Importantly, these results were validated in a 3D culture system with the sphere-forming and PC cell-derived organoid assays.ConclusionImipridones represent a novel approach to therapeutically target DRD2 and/or ClpP in PC. ONC206 shows more potent anti-cancer effects on PC cells than ONC201, paving the way for new effective therapeutics and better management of PC.

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).

No abstract available

Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.

P2, N=36, Not yet recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Jun 2023 --> Jun 2025 | Trial primary completion date: Dec 2022 --> Dec 2024

Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.

Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation.

Dopamine receptor signaling is implicated in various cancers including glioblastoma (GBM) and it is a recognized therapeutic target, as evidenced by recent clinical trials with a selective dopamine receptor D2 (DRD2) inhibitor ONC201...Thus, our findings demonstrate a molecular circuitry of oncogenic DRD2 signaling in which MET and TRAIL receptors, critical factors for tumor cell survival and cell death, respectively, govern GBM survival and death. Finally, tumor-derived dopamine and expression of dopamine biosynthesis enzymes in a subset of GBM may guide patient stratification for DRD2 targeting therapy.

Our data support the combination ONC201/Delta-24-RGD leads to a superior therapeutic effect due to the generation of a proinflammatory microenvironment in pHGG and DMGs preclinical models.

We treated DMG, GBM and HCC cells with imipridones, EHZ2i tazemetostat or HDACi panobinostat alone or combination of imipridones plus tazemetostat or panobinostat or the triple combination of imipridone plus tazemetostat and panobinostat. Shared regulated pathways in U251 included cell cycle arrest, cell adhesion, nervous system development, cell proliferation, negative regulation of proliferation, PERK-mediated unfolded protein response, extracellular matrix organization, regulation of transcription from RNA polymerase II promoter, and cellular response to hypoxia pathways. We conclude that imipridones ONC201, ONC206, and ONC212 which reduce EZH1 and EZH2 proteins share similar cytokine alterations, gene expression targets and actions with EZH2 inhibitors.