ulixertinib (BVD-523)

P2, N=1376, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> Jan 2027

Glioblastoma stem cell (GSC) lines and normal human astrocytes (NHAs) were treated with catalytic LSD1 inhibitors, NCD38 and bomedemstat, and the LSD1 scaffolding inhibitor, seclidemstat alone and in combination with kinase inhibitors, including osimertinib, afatinib, and ulixertinib. Combined treatment with NCD38 and osimertinib in glioblastoma-bearing mice delayed tumor growth and improved survival outcomes. These findings provide a rationale for further investigation of combination therapies of catalytic inhibitors of LSD1 and EGFR and dual-targeted inhibitors to overcome resistance and improve outcomes.

P1, N=20, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Sep 2025 --> Sep 2027

Despite the advent of venetoclax-based regimens, resistance mechanisms remain a major clinical challenge, particularly in patients with high-risk mutations such as TP53, MUC4, HLA-B and FLT3. Here, we evaluate two rational combination therapies, LY3009120 (pan-RAF) plus sapanisertib (mTOR) (LS), and ruxolitinib (JAK1/2) plus ulixertinib (ERK) (RU), across ten AML cell lines and a zebrafish embryo xenograft model...Mutation response analyses and clustering highlighted TP53, MUC4, HLA-B and FLT3 as correlates of LS and RU sensitivity, supporting mutation-informed prioritization. Collectively, our results nominate LS and RU as promising candidates, particularly in AML with TP53, FLT3, HLA-B or MUC4 alterations, and motivate prospective validation in stratified AML cohorts.

P2, N=6452, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

Our findings establish RAD21-mediated epigenetic regulation as a novel mechanism driving LUAD progression. The efficacy of ulixertinib in suppressing cancer metastasis in preclinical models highlights its translational potential for LUAD therapy.

We screened datasets associated with Gilteritinib and Quizartinib in the Gene Expression Omnibus (GEO) database for enrichment analysis and validated potential key pathways that may limit their therapeutic efficacy through qPCR and Western blot. Transcriptome sequencing revealed that these synergistic effects may stem from the regulation of gene expression such as PKD1, NR2E3, KDF1, and PRSS8 as well as modulation of ion channel activity. This in vitro study identifies aberrant activation of the RAS/MAPK pathway as a critical factor limiting the efficacy of FLT3 inhibitors in FLT3-ITD-positive AML and demonstrates the potent synergistic effects of Ulixertinib combined with FLT3 inhibitors in FLT3-ITD-positive AML cells, providing a novel therapeutic strategy for AML.

P1, N=45, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial primary completion date: Aug 2025 --> Jul 2026

Several molecules-such as SCH772984, SCH900353, ulixertinib (BVD-523), CC-9003, KO-947, AZD0364, norathyriol, and FR180204-are currently in preclinical or clinical trial stages. This review also highlights recent advances in the design and synthesis of ERK inhibitors, emphasising their structural uniqueness and potential to inhibit mutant forms of ERK1/2. Finally, we discuss future directions for the development of ERK1/2 inhibitors as FDA-approved cancer therapeutics.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Dec 2025 --> Dec 2026 | Trial completion date: Dec 2025 --> Dec 2026

Inhibition of MAPK1 by Ulixertinib, an orally active MAPK1 inhibitor, led to human bladder cancer growth inhibition in both 3D in vitro and in vivo models. In summary, screening for genes specifically driving 3D growth in immortalized cells may provide targets for both prevention and early therapy in bladder and other cancers while potentially limiting therapeutic toxicity.

P2, N=1376, Active, not recruiting, National Cancer Institute (NCI) | N=2316 --> 1376 | Trial completion date: Jun 2025 --> May 2026 | Trial primary completion date: Jun 2025 --> Mar 2025