Lymphomas are not infrequently associated with Epstein-Barr virus, with EBV-positivity linked to worse outcomes in several subtypes. Nanatinostat is a Class-I selective oral histone deacetylase inhibitor (HDACi) that induces expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This Phase 1b/2 study (NCT03397706) investigated the combination of nanatinostat with valganciclovir in patients aged >=18 with EBV+ lymphomas relapsed/refractory to >=1 prior systemic therapies with no viable curative treatment options. In the Phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended Phase 2 dose (RP2D) for Phase 2 expansion. Phase 2 patients (n=30) received the RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) in 28-day cycles. Primary endpoints were safety and RP2D determination (Phase 1b) and overall response rate (ORR; Phase 2). Overall, 55 patients were enrolled (B-NHLs [n=10], T/NK-NHLs [n=21], classical Hodgkin lymphoma [n=11], and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) [n=13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR] 19% [n=8]) with a median duration of response of 10.4 months. For T/NK-NHLs (n=15; all refractory to last prior therapy), the ORR/CRR was 60%/27%. The most common adverse events (AEs) were nausea (38% any grade) and cytopenias (Grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory Phase 2 study (NCT05011058) is underway.