P1/2, N=137, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile.

The safety profile of valemetostat monotherapy was acceptable in these patients with relapsed or refractory non-Hodgkin lymphoma. Favourable clinical activity was observed. These findings support a new indication for valemetostat in this setting.

P1/2, N=134, Not yet recruiting, Daiichi Sankyo

P2, N=474, Not yet recruiting, Alliance for Clinical Trials in Oncology

Additionally, while EZH1/2 inhibition impacts NOTCH signaling, the precise mechanism by which it affects M2-type tumor-associated macrophage (M2-TAM) polarization and germinal center expansion requires further investigation. Our research introduces EZH-1-P2 as a novel inhibitor with potential as a candidate for GCB DLBCL therapy, although further studies are needed to fully elucidate its mechanisms.

In this study, we found histone 3 lysine 27 (H3K27) demethylated by an inhibitor of histone methyltransferase EZH2 could epigenetically reverse the resistance to chemo-drug paclitaxel (PTX), or enhance the efficacy of immune checkpoint inhibitor anti-TIGIT via downregulating TIGIT ligand CD155. As results, local injection of OHG loaded with EZH2 inhibitor UNC1999, PTX and anti-TIGIT did not only synergistically enhance the cytotoxicity of PTX, but also reprogrammed the immune resistance via bi-directionally blocking TIGIT/CD155 axis, leading to the recruitment of cytotoxic effector cells into tumor and conferring a systemic immune memory to prevent lung metastasis. Hence, this polysaccharides-based OHG represents a potential in-situ epigenetic-, chemo- and immunotherapy platform to treat unresectable metastatic melanoma.

However, his condition became stable with the administration of valemetostat for 11 days, and subsequent low-dose-anticancer agents led to a rapid improvement accompanied by high fever and a surge in C-reactive protein. In this case, the in vivo priming effect of valemetostat on tumor cells may have increased the sensitivity of these cells to conventional anti-cancer drugs.

The target exposure range was established by defining a modified region of practical equivalence (184-887 ng·h/mL), which was expected to provide satisfactory efficacy and acceptable safety within the range of available exposure data. The simulated exposure range considering inter-individual variability showed that 200 mg could reach target exposure in the overall population and across subpopulations of interest, supporting the use of valemetostat 200 mg in patients with ATLL.

Dual-target inhibitors, exemplified by EZH1/2 inhibitor HH-2853(28), offer enhanced efficacy and reduced adverse effects. This review highlights recent advancements in dual inhibitors targeting EZH2 and other proteins like BRD4, PARP1, and EHMT2, emphasizing rational design, structure-activity relationships, and safety profiles, suggesting their potential in clinical applications.

P2, N=155, Active, not recruiting, Daiichi Sankyo | Trial completion date: Apr 2028 --> Sep 2025

Valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat may warrant further investigation in SCLC.

P1, N=210, Recruiting, Daiichi Sankyo | N=140 --> 210

Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 cancer patients correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, this data suggests that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents and may be beneficial in various indications with recurrent ARID1A mutations.

P1/2, N=45, Not yet recruiting, University of Alabama at Birmingham | Trial completion date: Dec 2027 --> May 2028 | Initiation date: May 2024 --> Oct 2024 | Trial primary completion date: May 2027 --> Oct 2027

P1, N=80, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2024 --> Dec 2026 | Trial primary completion date: Apr 2024 --> Dec 2026

P1/2, N=60, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2027 --> Sep 2025

P1/2, N=254, Recruiting, Haihe Biopharma Co., Ltd. | N=168 --> 254

P1/2, N=22, Terminated, Memorial Sloan Kettering Cancer Center | Completed --> Terminated; Due to DLTs

P1, N=140, Recruiting, Daiichi Sankyo | Trial completion date: Feb 2029 --> Nov 2028 | Trial primary completion date: Feb 2029 --> Nov 2028

In a recent publication, Yamagishi et al. explore how responses of a patient with adult T-cell leukemia/lymphoma to valemetostat, an EZH1/2 inhibitor, are associated with changes in H3K27me3, chromatin accessibility and gene expression, and how these changes can be circumvented in relapsed disease.

P2, N=148, Active, not recruiting, Daiichi Sankyo | Trial completion date: Sep 2025 --> Apr 2028

P1, N=140, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

The upregulation of EZH1 expression can promote the occurrence of HCC and lead to poor clinical progression and drug resistance; these effects may be mediated by regulating ATG7.

In this study, we used DNA or histone demethylating agents, 5-Azacytidine (5-AZA) or DS-3201 (valemetostat), respectively, to treat primary effusion lymphoma (PEL) cells, alone or in combination with AG490, a Signal transducer and activator of transcription 3 (STAT3) inhibitor. Differently from 5-AZA, the inhibition of the EZH1/2 histone methyltransferase by DS-3201, reported to contribute to STAT3 activation in other cancers, slightly affected STAT3 phosphorylation or survival in PEL cells, either alone or in combination with AG490. This study suggests that 5-AZA, by upregulating the expression level of SOCS3 and PTPN6/SHP1, reduced STAT3 activation and improved the outcome of treatment targeting this transcription factor in PEL cells.

P2, N=141, Active, not recruiting, The Lymphoma Academic Research Organisation | Recruiting --> Active, not recruiting | Trial completion date: Jun 2024 --> Oct 2024 | Trial primary completion date: Jun 2024 --> Oct 2024

P1/2, N=168, Recruiting, Haihe Biopharma Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

P1/2, N=45, Not yet recruiting, University of Alabama at Birmingham

Here we show the potency and mechanisms of action and resistance of the EZH1-EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma...We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.

P1, N=140, Not yet recruiting, Daiichi Sankyo, Inc.

Furthermore, analysis indicated that EZH1 and EZH2 bound competitively to PRC2 and influenced the methylation status of H3K27. In conclusion, our findings verified that EZH1 and EZH2 play opposing roles in OSCC and that EZH1 and EZH2 compete as the key component of PRC2, thus affecting the characteristics of OSCC via the methylation of H3K27.

P1, N=30, Recruiting, Lan Coffman | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2027 --> Jan 2027

Focusing on mutated SMARCA4 as the therapeutic target, growth inhibition assays showed a strong response to the CDK4/6 inhibitor palbociclib, but much less to the EZH1/2 inhibitor valemetostat. In conclusion, cell line TCS627 carries both histologic and genetic features characteristic of TCS and is a valuable model for both basic research and preclinical testing of new therapeutic options for treatment of TCS patients.

P1, N=30, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

We found that the addition of recombinant human IL-15 and the enhancer of zeste homolog 1/2 inhibitor UNC1999 promoted ILC3 generation...Finally, we observed that autologous HSPC mobilized from the blood of adults with hematological malignancies also developed into ILC3, albeit with a significantly lower capacity. Together, we developed a stroma-free protocol to generate large quantities of IL-22-producing ILC3 from healthy adult human HSPC that can be applied for adoptive transfer to prevent GvHD after allogeneic HCT.

No abstract available

The enhancer of zeste homolog 2 (EZH2) and its homolog EZH1 are catalytic components of polycomb repressive complex 2 (PRC2), which tri-methylate histone H3 at lysine 27 (H3K27me3) to repress transcription of their target genes. In conclusion, the present preclinical studies demonstrated that HM97662, an EZH1/2 dual inhibitor, had a promising and wide spectrum of therapeutic potential for hematological malignancies. It is urgent to assess the effectiveness of HM97662 in further clinical trials.

The EZH1/2 inhibitor valemetostat down-regulated EZH2 (p = 0... Our findings indicate that down-regulation of MLH1 through YY1/EZH2 inhibition plays a key role in the treatment of aggressive ATL.

P1; Phase classification: P1b --> P1

P1, N=30, Not yet recruiting, Lan Coffman | Trial completion date: Jan 2029 --> Jul 2029 | Initiation date: Sep 2023 --> Dec 2023 | Trial primary completion date: Oct 2025 --> Dec 2027

No treatment-related or grade ≥3 adverse events were reported. Appropriate valemetostat dose reductions are warranted when used concomitantly with strong CYP3A and P-gp dual inhibitors.

P1, N=30, Not yet recruiting, Washington University School of Medicine | Trial completion date: Sep 2029 --> Dec 2029 | Initiation date: Sep 2023 --> Dec 2023 | Trial primary completion date: Oct 2027 --> Jan 2028