Beleodaq (belinostat)

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

The purpose of this research was to provide insight on the specific molecular processes through which belinostat inhibits HDAC. The ability to investigate new therapeutic options employing targeted therapy and acquire a deeper understanding of cancer cell abnormalities may result from a better understanding of these particular routes.

Several HDACi drugs like vorinostat, romidepsin, panobinostat, and belinostat are approved by the Food and Drug Administration. China and Japan have approved the use of tucidinostat, a new subtype-selective HDACi that inhibits class 1 HDAC1, HDAC2, HDAC3, as well as class 2b HDAC10...This review highlights the HDACi classes, the mechanism of action of these inhibitors, their preclinical and clinical efficacy, and the latest clinical trials and patents used in cancer therapeutics. Overall, this review focuses on patents and clinical trials data from 2019 onward to give a better viewpoint on current trends in HDACis as chemotherapy agents.

Several HDACis, such as romidepsin, belinostat, and chidamide, have demonstrated favorable clinical efficacy and safety in PTCLs. Mutation analysis based on next-generation sequencing may advance our understanding of the correlation between epigenetic mutation profiles and relevant targeted therapies. Multitargeted HDACis and HDACi-based prodrugs hold promising futures and offer further directions for drug design.

P1, N=9, Suspended, University of Utah | Trial completion date: Nov 2025 --> Nov 2026 | Trial primary completion date: Nov 2023 --> Nov 2024

Another HDACi panobinostat also showed potential anticancer effect in both H358 and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing KRAS-mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for preclinical and clinical studies.

P1, N=30, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Jul 2023 --> Jul 2024

In addition, the pooled CR rate was 17% (95% CI, 13-22%), 10% (95% CI, 5-15%), and 10% (95% CI, 5-15%) in the romidepsin, belinostat, and chidamide monotherapy subgroups, respectively. The combination of HDAC inhibitor and chemotherapy exhibited superior efficacy to HDAC inhibitor monotherapy in the R/R PTCL setting. Additionally, HDAC inhibitor-based therapy had higher efficacy in angioimmunoblastic T-cell lymphoma patients than that in other subtypes.

There are several approved agents for the treatment of relapsed T-cell lymphomas including pralatrexate, romidepsin, belinostat, and brentuximab vedotin, but none of them are considered curative. As these studies mature, it is expected that the treatment for TCL will evolve so that each individual patient will be treated based on the biologic and molecular characteristics of their tumor type. The future for TCL remains promising.

Among the four ligands belinostat compound showed best binding affinity with histone deacetylase protein which was -8.7 kJ/mol. It also formed five conventional hydrogen bond with Gly 841, His 669, His 670, pro 809, and His 709 amino acid residues.

This mutant IDH1 tumor appeared to display greater sensitivity to the addition of belinostat than the other cases with wild-type IDH tumors based on both standard magnetic resonance imaging (MRI) and advanced spectroscopic MRI criteria. These data together suggest that IDH mutation status within gliomas may serve as a biomarker of response to HDACis.

P1, N=39, Suspended, Mayo Clinic | Trial completion date: May 2023 --> May 2026 | Trial primary completion date: Apr 2023 --> Apr 2025

Downstream inhibition of MAZ-NF1 chimeric transcript in an ALK- ALCL PDX using MEK-inhibitor AZD6244 produced a delay in tumor growth in-vivo...Finally, we trained a predictive model based on RNAseq data and viability upon drug exposure and found gene sets predicting response to specific compounds (i.e., ruxolitinib and belinostat)...1D) and showed close correspondence with patients' responses to various drugs, including chemotherapy (CHOP) as well as targeted agents (ALK-inhibitor crizotinib, JAK-inhibitor ruxolitinib, CD30-drug conjugate brentuximab-vedotin). In addition, we tested novel compounds emerging from the drug screenings including JAK/SYK inhibitor cerdulatinib and CDK9 inhibitor AZD4573: mice treated with the combination of the two drugs showed significantly better progression-free survival compared to single agents... We generated the largest TCL PDX bio-repository accounting for >90 models of different subtypes. PDXsmimicked donor lymphomas phenotypically and genotypically. We discovered novel driver fusions, oncogenic mutations, clonal evolution patterns, innovative therapeutics/combinations and response predictors.

Background: The BCL-2 inhibitor venetoclax, in combination with hypomethylating agents (HMA) or low dose cytarabine, has been introduced to clinical practice as an alternative for AML patients unfit for intensive chemotherapy... We demonstrate that sensitivity to venetoclax and navitoclax correlates with sensitivity to the HDAC inhibitors belinostat, panobinostat and vorinostat in samples from AML patients with relapsed disease (N = 53)...We demonstrated that small doses of HDAC inhibitors, non-toxic as a single agent, can resensitize AML cells to venetoclax and navitoclax by induction of irreversible DNA damage.

P1, N=34, Recruiting, University of Utah | Trial completion date: Aug 2025 --> Aug 2026 | Trial primary completion date: Aug 2023 --> Aug 2024

P2, N=29, Active, not recruiting, Emory University | Trial completion date: Aug 2022 --> Aug 2024 | Trial primary completion date: Aug 2022 --> Aug 2023

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

P1, N=64, Recruiting, National Cancer Institute (NCI) | N=48 --> 64