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Clinical Trial
. 2025 Mar 3;31(5):815-823.
doi: 10.1158/1078-0432.CCR-24-2814.

First-in-Human Clinical Trial of a Small-Molecule EBNA1 Inhibitor, VK-2019, in Patients with Epstein-Barr-Positive Nasopharyngeal Cancer, with Pharmacokinetic and Pharmacodynamic Studies

A Dimitrios Colevas  1 , Zahra Talebi  2 , Elizabeth Winters  3 , Caroline Even  4 , Victor Ho-Fun Lee  5 , Maura L Gillison  6 , Saad A Khan  1 , Rong Lu  7 , Benjamin A Pinsky  8 , Samantha S Soldan  9 , Olga Vladmirova  9 , Paul M Lieberman  9 , Troy E Messick  9
Affiliations
Clinical Trial

First-in-Human Clinical Trial of a Small-Molecule EBNA1 Inhibitor, VK-2019, in Patients with Epstein-Barr-Positive Nasopharyngeal Cancer, with Pharmacokinetic and Pharmacodynamic Studies

A Dimitrios Colevas et al. Clin Cancer Res. .

Abstract

Purpose: A first-in-human phase I study was conducted in patients with nasopharyngeal carcinoma to assess the safety and tolerability of VK-2019, a small-molecule selective inhibitor of Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1).

Patients and methods: Pharmacokinetic and pharmacodynamic studies were performed, including the measurement of EBV DNA plasma levels. Twenty-three patients received VK-2019 orally once daily at doses ranging from 60 to 1,800 mg using an accelerated titration design, with cohort expansion at 1,800 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 EBV DNA plasma levels were observed in some patients. VK-2019 reduced EBV genome copy number and viral gene expression in patient tumor samples and induced changes in immune cell markers.

Conclusions: VK-2019 at dosages up to 1,800 mg daily demonstrated an acceptable safety profile, achieved micromolar plasma concentrations, and showed on-target biological activity in tumors from patients with advanced EBV-positive nasopharyngeal carcinoma.

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Conflict of interest statement

Conflicts of Interest

The Wistar Institute, on behalf of authors Troy E. Messick and Paul M. Lieberman, has filed patents covering composition of matter and their use on the small molecule disclosed here for the treatment of human cancer and other diseases (patent number WO2015073864, “EBNA1 Inhibitors and Their Method of Use”; WO2016183534, “EBNA1 Inhibitors and Methods using Same”). Paul M. Lieberman is a founder and advisor to Vironika, LLC, and has served as consultant for GSK and Sanofi. All other authors declare no competing interests.

Figures

Figure 1.
Figure 1.
Time on treatment and Treatment response. Individual patient duration on treatment and time of best RECIST response: Partial Response (PR), Stable disease (SD), Progressive Disease (PD), Not Evaluated (NE). Black dot denotes the time that the response was recorded.
Figure 2.
Figure 2.
Plasma concentrations following single (cycle 1 day 0) and multiple dose (cycle 1 day 14) of VK-2019. A. Mean concentrations for each dose cohort after single dose. B. Mean concentrations for each dose cohort after multiple doses. Error bars indicate standard deviation. C. Plot of Cmax after single dose and multiple doses at different dose levels. D. Plot of AUC0-24h after single dose and multiple doses at different dose levels. Solid circles are from the single dose (Cycle 1 Day 1) and open circles are from multiple dose (Cycle 1 Day 14) PK data.
Figure 3.
Figure 3.
Response to treatment of select patients and biomarker analysis. A. Tumor volume of patient 13 at 1800 mg daily dose who experienced RECIST PR during treatment. B. Change in EBV genome copy number per cell from biopsies taken from patients 10, 13 and 14. C. EBER-ISH of tumor material taken from patient 14. D. Changes in plasma EBV DNA of patients at the 1800 mg/day dose level. Baseline level = 1.
Figure 4.
Figure 4.
A. Digital spatial profiling analysis of gene expression of biopsies before treatment (baseline) and after treatment (treatment) from three patients. A. Heatmap of differentially expressed genes. B. Volcano plot depictions of the log2(fold-change) in gene expression on the x-axis and negative log10(p value) on the y-axis for gene expression. C. Box and whisker plots displaying gene expression counts from three patients. Statistical testing was performed using Mann-Whitney non-parametric T-tests.
See this image and copyright information in PMC

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