SAFETY AND EFFICACY FINDINGS OF A PHASE 1B/2 STUDY OF NANATINOSTAT PLUS VALGANCICLOVIR FOR TREATMENT OF RELAPSED/REFRACTORY EPSTEIN-BARR VIRUS-POSITIVE DIFFUSE LARGE B-CELL LYMPHOMA

Background: Diffuse large B-cell lymphoma (DLBCL) is one of several lymphoid malignancies in which Epstein-Barr virus (EBV) can play a significant role in pathogenesis. An estimated 5–14% of DLBCL cases are linked to EBV, which is associated with poor prognosis and 5-year survival rates as low as 25%. EBV is an attractive and druggable, but largely untapped, non-host tumor target, partly due to its latency. Most EBV genes, including those of the lytic cycle, are epigenetically silenced, preventing effective viral targeting. However, reactivation of viral gene expression with a histone deacetylase inhibitor (HDACi), combined with a DNA synthesis inhibitor, such as ganciclovir and its oral prodrug valganciclovir (VGCV), is an effective strategy to induce EBV+ tumor cell apoptosis. The safety and efficacy of this novel therapeutic strategy was investigated here using the HDACi nanatinostat (Nstat) and VGCV in patients (pts) with EBV-positive (EBV+) DLBCL. Methods: This Phase 1b/2 study (NCT03397706) assessed Nstat+VGCV in pts aged ≥18 years with EBV+ relapsed/refractory lymphoid malignancies. For inclusion, pts must have had ≥1 prior systemic therapies and no viable curative treatment options. Phase 1b evaluated safety and defined the recommended Phase 2 dose of Nstat+VGCV. Safety was assessed from first drug administration until 28 days post-last dose or until the start of a new anticancer therapy. Phase 2 assessed efficacy (overall response rate [ORR]). Here, subgroup analysis data of pts with DLBCL are reported. Results: Ten pts with DLBCL were included in the Safety Analysis Set. The median age was 76 years, 70% of pts were male and 80% had stage 3–4 disease. At the data cut-off (May 4, 2023), all pts had reported ≥1 treatment-emergent adverse event (TEAE). The most common any-grade TEAEs were fatigue (n = 8, 80%), neutropenia (n = 6, 60%), anemia, and decreased platelet count/thrombocytopenia (both n = 5, 50%). The most common grade ≥3 TEAEs were neutropenia (n = 5, 50%), anemia (n = 3, 30%), and decreased white blood cell/lymphocyte count (n = 2, 20%). The most common any-grade TEAEs related to the study drugs were fatigue, neutropenia (both n = 6, 60%), anemia, and decreased platelet count/thrombocytopenia (both n = 4, 40%). Five pts (50%) reported ≥1 serious TEAE. Four pts (40%) experienced study drug-related serious adverse reactions, namely atrial fibrillation (n = 2, 20%), febrile neutropenia, and myelodysplastic syndrome (both n = 1, 10%). No deat