Abstract. Purpose: A first-in-human phase one study was conducted in nasopharyngeal carcinoma (NPC) patients to assess the safety and tolerability of VK-2019, a small molecule selective inhibitor of Epstein-Barr virus Nuclear Antigen 1 (EBNA1). Patients and Methods: Pharmacokinetic and pharmacodynamic studies, including circulating tumor EBV DNA plasma levels, were performed. Twenty-three patients received VK-2019 orally once daily at doses ranging from 60 to 1800 mg using an accelerated titration design, with cohort expansion at 1800 mg. EBV genome copy number and spatial transcriptomic analyses were conducted on biopsies collected from three patients at baseline and after treatment. Results: VK-2019 was well tolerated. One patient achieved a partial response. Pharmacokinetic results demonstrated good systemic exposure, with high intersubject variability. Decreases in circulating tumor EBV DNA plasma levels were observed in some patients. VK-2019 reduced EBV genome copy number and vir