Efficacy and safety of ifupinostat (BEBT-908) in combination with rituximab for relapsed/refractory diffuse large B-cell lymphoma: Results from an exploratory phase Ib study.

7050 Background: Ifupinostat is a dual HDAC/PI3Kα inhibitor designed to target tumor cell signaling networks by simultaneously inhibiting HDAC and PI3Kα, thereby disrupting tumor cell proliferation and inducing apoptosis. A single-arm pivotal trial of Ifupinostat in patients who received at least two lines of systemic therapy for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) has been completed, with data currently under NDA review by the NMPA. This exploratory trial evaluates Ifupinostat in combination with rituximab as part of a confirmatory phase 3 trial to further assess its efficacy and safety as a second-line treatment for r/r DLBCL (NCT06164327). Methods: This multicenter Phase 1b trial was designed to evaluate the efficacy and safety of Ifupinostat in combination with rituximab (R) with or without standard second-line regimens (R-GemOx or R-ICE). Cohort 3 included 24 r/r DLBCL patients with prior exposure to at least one systemic therapy, all involving anti-CD20 antibody. Among these, 16 patients (66.6%) were primary refractory, 4 patients (16.7%) were refractory to their most recent line of therapy, and 4 patients (16.7%) were relapsed cases. Treatment consisted of Ifupinostat administered intravenously at a dose of 22.5 mg/m² on days 1, 3, 5, 8, 10, and 12 of each 21-day cycle. Rituximab was administered intravenously at a dose of 375 mg/m² on day 1 of each cycle. Tumor assessments were conducted following treatment, and efficacy was evaluated according to the Lugano 2014 criteria. Key endpoints included the objective response rate (ORR) and safety. Results: Of the 24 enrolled patients, 21 completed at least one treatment dose and underwent tumor assessment. The ORR was 76.2%, with 10 patients (47.6%) achieving a complete response (CR) and 6 (28.6%) achieving a partial response (PR). The disease control rate (DCR) was 85.7%. Median progression-free survival (PFS) has not yet been reached (>7.7 months). Common grade 3-4 hematological toxicities observed during treatment included thrombocytopenia (34.8%), leukopenia (17.4%), and lymphopenia (13.0%). No unexpected toxicities were observed, and the safety profile was deemed manageable. Conclusions: The study results demonstrate promising efficacy and a manageable safety profile for Ifupinostat in combination with rituximab as a second-line treatment for r/r DLBCL. These findings support further investigation in confirmatory phase 3 trials, which are currently underway. Clinical trial information: NCT06164327 .