BMS-986158

P1/2, N=216, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Apr 2027 --> May 2026 | Trial primary completion date: Apr 2025 --> May 2026

P1, N=41, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | N=66 --> 41 | Trial completion date: Jun 2025 --> Jul 2024

P1/2, N=216, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P1/2, N=220, Recruiting, Bristol-Myers Squibb | Phase classification: P1b/2a --> P1/2

Similar synergistic effects were found when combining GOLCA with JQ1, another tool compound BET inhibitor, confirming BET inhibition potentiates the anti-DLBCL effects of the CELMoD agent. BET inhibition potentiates anti-proliferative effects of GOLCA in DLBCL cells through synergistic induction of p21 and inhibition of E2F signaling. The synergetic effects of BMS-986158 and GOLCA suggest potential clinical benefits of combining lower doses of single agents to achieve better efficacy with reduced risk of adverse effects.

P1/2, N=216, Recruiting, Bristol-Myers Squibb | Phase classification: P1b/2 --> P1/2

In combination with Janus kinase inhibitors (JAKi), ruxolitinib (RUX) or fedratinib (FED), BET inhibitors (BETi) have been shown to reduce inflammatory signals and disease burden in preclinical models of MF. 2023) were observed as expected. Conclusions Preliminary data suggest combination treatment with BMS-986158 and JAKi in MF may modulate JAK2 VAF, BM microenvironment, circulatory cytokines, and other SF, providing evidence of early disease modifying potential of these drug combinations.

The reductions observed in JAK2 VAF provide promising preliminary data of potential disease modification. Dose expansion with BMS-986158+RUX in 1L MF has opened and is actively enrolling patients.

Objective: Standard of care drugs for rhabdomyosarcoma (RMS), such as vincristine and doxorubicin, have a high systemic toxicity and >70% of high-risk patients develop resistance... ARMS cell lines (RH4, RH30) were treated with BETi compounds (BMS-986158, PLX51107) using a 12-point serial dilution (2.6 nM-10 M)... Functional validation confirmed BETi's potential for in vivo ARMS studies. Ongoing clinical trials of the primary drug candidate, BMS-986158, in childhood cancers increases the likelihood of clinical trial opportunities in RMS. Our metastatic models demonstrate clinical relevance and BETi sensitivity, crucial for addressing the lack of established metastatic ARMS studies.

Using a combination of patient and syngeneic murine models, we investigated the effects of the BETi drug BMS-986158 on cellular proliferation, organoid growth, cell-cycle progression, and mitochondrial metabolic disruption. These were investigated independently and in combination with standard cytotoxic chemotherapy (gemcitabine + paclitaxel [GemPTX])...We demonstrated mechanistic and functional data that BETi induces metabolic mitochondrial dysfunction, abrogating PDAC progression and proliferation, alone and in combination with systemic cytotoxic chemotherapies. This novel approach improves the therapeutic window in patients with PDAC and offers another treatment approach distinct from cytotoxic chemotherapy that targets cancer cell bioenergetics.

P1, N=66, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Jun 2024

We finally test the most potent molecule, inhibitor BMS-986158, in an orthotopic PDX mouse model of FP-RMS with additional high-risk mutations, and find that it is well tolerated in vivo and leads to an average decrease in tumor size. This effort represents a partnership with an FP-RMS patient and family advocates to make preclinical data rapidly accessible to the family, and to generate data to inform future patients who develop this disease.

P1, N=66, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Jul 2023 --> Dec 2023

Thus, the goal of this study is to explore the molecular mechanisms behind promising epigenetic inhibitors in RMS, focusing on embryonal RMS, and to test these drugs in vivo in combination with vincristine. Our laboratory obtained a selection of epigenetic compounds from the Ontario Institute of Cancer Research (OICR) and Structural Genomics Consortium (SGC) that mainly target BET (BMS-986158, I-BET151, PLX51107) or HDAC (Apicidin, Domatinostat, Fimepinostat) proteins...Furthermore, the level of apoptosis in this cell line was higher after treatment with PLX51107 than after treatment with the positive control, doxorubicin (Figure 3)... Our data suggest that BET inhibitors may exploit an epigenetic weakness of ERMS, perhaps related to MYC amplification. In the future, we plan to conduct transcriptome assays to explore the mechanism of action of BET inhibitors in ERMS, and in vivo drug combination studies in an ERMS mosaic mouse model and patient-derived xenografts (PDXs).

Furthermore, BMS-986158 exerted strong synergism in reactivating latent HIV-1 when combined with prostratin and vorinostat and enhanced the antiviral activity of anti-HIV-1 drugs. Finally, BMS-986158 showed antiviral activity in an HIV-1 acute infection model, possibly by arresting the cell cycle in infected cells. Thus, these results suggest that BMS-986158 is a potential candidate for AIDS/HIV-1 therapy.

P1, N=66, Recruiting, Dana-Farber Cancer Institute | N=34 --> 66 | Trial primary completion date: Jul 2022 --> Jul 2023

Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.

Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous system-penetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation. This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.