Beleodaq (belinostat)

P2, N=32, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2025 --> Jun 2025 | Trial primary completion date: Jan 2025 --> Jun 2025

P2, N=32, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Sep 2025

Dexamethasone (Dex) treatment resulted in a significant difference in cell migration rates in two CRC cell lines with disparate GR expression levels...Belinostat, the selected compound, was successfully validated for its potential to counteract the effects of GC-induced invasion in CRC cells in vitro...This study provides valuable insights into the molecular mechanisms underlying GC-induced metastasis, introducing newly repositioned compounds that could serve as potential adjuvant therapy to GC treatment. Furthermore, it opens avenues for exploring novel drug candidates for CRC treatment.

In vitro study showed that both the pan-HDAC inhibitor belinostat, class I and class IIa HDAC inhibitor valproic acid, and selective HDAC1 inhibitor parthenolide induce morphology alteration, proliferation inhibition, expression of neuronal markers including microtubule-associated protein 2, neuronal nuclei antigen, and synaptophysin in U87 cells. This study suggests that the HDAC inhibitors belinostat, valproic acid, and parthenolide can induce glioma cells to differentiate into neuron-like cells, with HDAC1/3/7 being the likely drug targets and HDAC1 potentially playing an important role in this.

In vivo experiments also showed that PXD101 combined with radiotherapy could significantly inhibit the growth of GBM. This study provides experimental evidence for application of the novel HDACi PXD101 in the treatment of GBM, as well as new molecular markers and potential intervention targets that may be used in preventing GBM malignant progression and radioresistance.

P1, N=26, Active, not recruiting, University of Michigan Rogel Cancer Center | Recruiting --> Active, not recruiting

P1, N=34, Recruiting, University of Utah | Trial primary completion date: Aug 2024 --> Apr 2024

P1, N=64, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P3, N=150, Recruiting, Corvus Pharmaceuticals, Inc. | Not yet recruiting --> Recruiting

P1, N=64, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P2, N=15, Active, not recruiting, University of Miami | Recruiting --> Active, not recruiting | N=10 --> 15 | Trial completion date: Dec 2025 --> Jul 2025 | Trial primary completion date: Dec 2024 --> Jul 2024

P3, N=150, Not yet recruiting, Corvus Pharmaceuticals, Inc.

P1, N=30, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Jun 2025 | Trial primary completion date: Jul 2024 --> Jun 2025

P2, N=50, Recruiting, University of Virginia | Trial primary completion date: Dec 2026 --> Jun 2026

P1, N=25, Recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Jul 2024 --> Dec 2024

Drug sensitivity analysis identified numerous correlations, with CXCL13 and HAVCR2 expressions influencing sensitivity to several drugs, including Apitolisib, Belinostat, and Docetaxel. Overall, these findings highlight the importance of reviving exhausted T cells to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes.

P2, N=50, Recruiting, University of Virginia | Trial primary completion date: Jun 2026 --> Dec 2026

P2, N=50, Recruiting, University of Virginia | Phase classification: P2b --> P2 | Trial primary completion date: Jun 2024 --> Jun 2026

P2, N=32, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P2, N=60, Not yet recruiting, National Cancer Institute (NCI)

Four drugs in this category have received approval from the U.S. Food and Drug Administration (FDA) for use: Panobinonstat (though canceled by the FDA in 2022), Vorinostat, Belinostat and Romidepsin. This review provides a comprehensive evaluation of the clinical efficacy and safety data pertaining to the currently approved histone deacetylase inhibitors, as well as an explanation of the crucial function of histone deacetylase in multiple myeloma and the characteristics of the different histone deacetylase inhibitors. Moreover, it provides a concise overview of the most recent developments in the use of histone deacetylase inhibitors for treating multiple myeloma, as well as potential future uses in treatment.

These hepatic impairment effects reduced between-subject variability by only 5%-8% for their respective parameter, with a large amount of remaining unexplained variability. With further validation, this model can be leveraged to assess the need for dose adjustments in this patient population.

P1, N=64, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

Researchers across the globe have identified various small molecules like benzo[d][1,3]dioxol derivatives, belinostat analogs, pyrazine derivatives, quinazolin- 4-one-based derivatives, 2,4-imidazolinedione derivatives, acridine hydroxamic acid derivatives, coumarin derivatives, tetrahydroisoquinoline derivatives, thiazole-5-carboxamide, salicylamide derivatives, β-peptoid- capped HDAC inhibitors, quinazoline derivatives, benzimidazole and benzothiazole derivatives, and β- elemene scaffold containing HDAC inhibitors. Most of the scaffolds have shown attractive IC50 (μM) in various cell lines like HDAC1, HDAC2, HDAC6, PI3K, HeLa, MDA-MB-231, MCF-10A, MCF-7, U937, K562 and Bcr-Abl cell lines.

Belinostat has a potential effect on the differentiation and self-renewal of breast CSCs.

P1, N=25, Recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Dec 2023 --> Jul 2024 | Trial primary completion date: Dec 2023 --> Jul 2024

P2, N=32, Suspended, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=10, Recruiting, University of Miami | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

To identify alternative mechanisms of resistance to romidepsin, we selected MCF-7 breast cancer cells with romidepsin in the presence of the P-gp inhibitor verapamil to reduce the likelihood of P-gp-mediated resistance. The resulting cell line, MCF-7 DpVp300, does not express P-gp and was found to be selectively resistant to romidepsin but not to other HDACis such as belinostat, panobinostat, or vorinostat. RNA sequencing analysis revealed upregulation of the mRNA coding for the putative methyltransferase, METTL7A, whose paralog, METTL7B, was previously shown to methylate thiol groups on hydrogen sulfide and captopril...We demonstrate that expression of METTL7A or METTL7B confers resistance to thiol-based HDACis and that both enzymes are capable of methylating thiol-containing HDACis. We thus propose that METTL7A and METTL7B confer resistance to thiol-based HDACis by methylating and inactivating the zinc-binding thiol.

We find that patients treated with standard-of-care therapy plus Belinostat, that also had lower volumes of undertreated tumor detected by sMRI, had better survival outcomes highlighting the potential of integrating sMRI with Belinostat. *Clinical Relevance/Application: In this retrospective analysis of GBM patients treated with Belinostat, we aim to determine if there is a relationship between undertreated lesion detected by sMRI and survival.

In the context of histone H3 acetylation (H3KAc), panobinostat increased H3KAc, on average, by 7.6-fold and 30.5-fold in IDHwt and IDHmut glioma cultures, respectively (p < 0.001)...IDHmut gliomas are more sensitive two other FDA-approved HDACis: belinostat and vorinostat...Furthermore, using a PDX glioma model, we show that only mice engrafted with IDHmut glioma exhibit a significant survival increase in response to the HDACi belinostat: median survival was extended by 14 days in IDHmut glioma-bearing mice (p= 0.01), whereas belinostat extended median survival by 4 days in IDHwt glioma-bearing mice (p= 0.11). These results suggest that HDACi may be an effective in treating IDHmut gliomas.

Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead significantly enhances its metabolic stability in vitro and targets anti-cancer pathways by perturbing key MRs in colon cancer. Complexation of HDACis to a metal ion might improve the efficacy of clinically used HDACis in patients with colon cancer.

P3, N=504, Recruiting, Acrotech Biopharma Inc. | Not yet recruiting --> Recruiting

Other epigenetic therapies, such as tazemetostat and belinostat, are approved for use in follicular and T-cell lymphoma, respectively, but have limited single agent activity in DLBCL. In summary, these data propose YF2 combination epigenetic therapy as a means to increase immunogenicity in CBP/p300- and EZH2-mutated DLBCL. While our preliminary mouse experiment provided promising initial results, an expanded study is underway to statistically confirm the exciting trends that we observed.

In addition, we generated a belinostat-resistant H9 cell line (H9-belino-R) by incrementally exposing H9 to increasing concentrations of belinostat...H9-belino-R retained significant resistance to other HDAC inhibitors such as romidepsin [(H9: IC50 = 0.97nM (SEM ± 0.030), H9-belino-R: IC50 = 1.38nM (SEM ± 0.028)] and panobinostat [H9: IC50 = 3.11nM (SEM ± 0.19), H9-belino-R: IC50 = 9.00nM (SEM ± 1.55)] as measured by the CellTiter-Glo Viability Assay...These preliminary findings provide us with evidence that suggests that the combination of YF2 and ruxolitinib can serve as a novel treatment combination for CTCL. Further study is planned to explore this treatment in murine models of disease.

P1, N=9, Recruiting, University of Utah | Suspended --> Recruiting

P3, N=504, Not yet recruiting, Acrotech Biopharma Inc.

Notably, only one of these 10 drugs, panobinostat, has been approved for use in MM. The two most promising genes, calcium signal-modulating cyclophilin ligand (CAMLG) and histone deacetylase 2 (HDAC2), were targeted by four drugs (cyclosporine, belinostat, vorinostat, and romidepsin), all of which have clinical evidence supporting their use in the treatment of MM. Interestingly, five of the 10 drugs have been approved for other indications than MM, but they may also be effective in treating MM. Therefore, this study aimed to clarify the genomic variants involved in the pathogenesis of MM and highlight the potential benefits of these genomic variants in drug discovery.

P1, N=64, Recruiting, National Cancer Institute (NCI) | Initiation date: Dec 2022 --> Mar 2023

P1, N=25, Recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Jul 2023 --> Dec 2023 | Trial primary completion date: Jul 2023 --> Dec 2023