fimepinostat + venetoclax

Fimepinostat + venetoclax is an oral combination therapy under clinical investigation for hematologic malignancies, notably **relapsed or refractory diffuse large B-cell lymphoma (DLBCL)** and **high-grade B-cell lymphoma (HGBL)** with MYC and BCL2 gene rearrangements (e.g., double-hit lymphoma, triple-hit lymphoma, double-expressor lymphoma)[1][3][5]. Fimepinostat is a dual inhibitor of phosphoinositide 3-kinase (PI3K, isoforms α, β, δ) and histone deacetylases (HDACs) type 1/2; it suppresses MYC activity and downstream oncogenic pathways[1][3][7]. Venetoclax is a highly selective, oral small molecule inhibitor of BCL2, a key anti-apoptotic protein commonly overexpressed in B-cell malignancies[1][3][4][5][7]. Nonclinical data and early-phase clinical trials show **synergistic anti-tumor activity** when the two agents are combined, particularly in models harboring MYC/BCL2 co-alterations and in settings where resistance to single agents emerges[1][3][7]. Fimepinostat helps overcome resistance to venetoclax by downregulating anti-apoptotic and cell-cycle regulatory proteins (e.g., MCL1, CHK1, WEE1, c-MYC), upregulating pro-apoptotic proteins (e.g., BIM), and inducing DNA damage[7]. Combination therapy is administered orally (fimepinostat 5-days-on/2-days-off with daily venetoclax), and has been tested in Phase 1/2 trials to determine safety, maximum tolerated dose, and preliminary efficacy[1][3][5].