DOSE FINDING STUDY TO ASSESS SAFETY, PK AND EFFICACY OF FIMEPINOSTAT (CUDC-907) WITH VENETOCLAX OR RITUXIMAB PLUS BENDAMUSTINE IN PATIENTS WITH RELAPSED/REFRACTORY LYMPHOMA

Background: The 2016 WHO reclassification of lymphoid tumors distinguishes double-hit (DHL) and triple-hit (THL) lymphomas as clinically important subtypes, now classified as high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements. Double-expressor lymphoma with MYC and BCL2 protein overexpression without rearrangement (included within DLBCL-NOS) also has prognostic importance. This reclassification highlights the dismal outcomes for patients with tumors harboring MYC and/or BCL2 alterations. Currently, there are no approved therapies that target MYC. Fimepinostat (F) is an investigational small-molecule dual inhibitor of PI3Ks and HDACs. F inhibited both PI3K and HDAC in non-clinical studies and substantially reduced MYC protein levels. PI3K and HDAC were also inhibited by F in patients. F demonstrated synergistic anti-tumor effects with venetoclax (V) in DHL and DEL models in vitro and in vivo. In clinical studies, F as monotherapy or in combination with rituximab (R) was well tolerated with a favorable safety profile in patients with R/R lymphoma, and resulted in robust and durable objective response rates (ORR) in patients with R/R MYC-altered DLBCL. Methods: CUDC-907-101 is a Phase 1/2, multi-center, dose-finding study that was recently amended to study F in combination with V, or F with R plus bendamustine (B) in pts with R/R lymphoma, including DLBCL or HGBL with MYC and BCL2 alterations. The primary objectives are to determine the MTD, safety and tolerability of each combination, and to assess preliminary efficacy, as measured by ORR and DOR. Pts must be R/R to ≥1 prior regimen, have measurable disease (Lugano criteria), and have archived or fresh tumor tissue. Approximately 12 pts (dose escalation; 3+3 design) and 30 pts (dose expansion) will be enrolled into each combination arm. Clinical trial: NCT01742988. 1: F 30 mg daily, 5/2 + V 400 mg QD 2: F 60 mg daily, 5/2 + V 400 mg QD 3: F 60 mg daily, 5/2 + V 800 mg QD 1: F 30 mg daily, 5/2 + B 90 mg/m2 Day 1,2 + R 375 mg/m2 Day 1 2: F 60 mg daily, 5/2 + B 90 mg/m2 Day 1,2 + R 375 mg/m2 Day 1 3: F 60 mg daily, 5/2 + B 120 mg/m2 Day 1,2 + R 375 mg/m2 Day 1 Keywords: “double-hit” lymphomas; high-grade B-cell lymphoma with or without rearrangement of MYC and BCL2 and/or BCL6; MYC. Disclosures: Younes, A: Consultant Advisory Role: BMS, Incyte, Janssen, Genentech and Merck; Honoraria: Genentech, Merck, Takeda, Incyte, BMS, AbbVie; Research Funding: Novartis, Johnson & Johnson, Curis, Roche, BMS.