Phase I and II Clinical Studies of the STING Agonist Ulevostinag with and without Pembrolizumab in Participants with Advanced or Metastatic Solid Tumors or Lymphomas

作者：Kevin J. Harrington, Stéphane Champiat, Joshua Brody, Byoung Chul Cho, Emanuela Romano, Talia Golan, John Hyngstrom, James Strauss, David Y. Oh, Aron Popovtzer, Carlos Gomez‐Roca, Ruth Perets, Sung‐Bae Kim, Deborah J. Wong, Steven Powell, Anuradha Khilnani, Thomas Jemielita, Qing Zhao, Runchen Zhao, Matthew Ingham · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-24-3630 · 被引用次数：40 · 研究领域：interferon and immune responses、Cancer Immunotherapy and Biomarkers、Cytokine Signaling Pathways and Interactions

PURPOSE: We report results from two clinical trials of the cyclic dinucleotide stimulator of IFN genes (STING) agonist ulevostinag. PATIENTS AND METHODS: In a phase I study (NCT03010176) with an accelerated titration design/modified toxicity probability interval method, participants with advanced/metastatic solid tumors or lymphomas received intratumoral ulevostinag (±intravenous pembrolizumab). In an expansion phase, participants with head and neck squamous cell carcinoma (HNSCC) or triple-negative breast cancer received the combination. Primary objectives were safety/tolerability and identifying the recommended phase II dose; biomarkers were exploratory. In a randomized phase II study (NCT04220866), participants with untreated metastatic or unresectable, recurrent HNSCC received intravenous pembrolizumab (±ulevostinag 540 µg). The primary objective was antitumor activity. Pembrolizumab 200 mg was administered every 3 weeks in both studies. RESULTS: In the phase I study (NCT03010176; N = 156), the most common adverse event was pyrexia (70%). Plasma ulevostinag concentrations increased dose-dependently. Circulating levels of C-X-C motif chemokine 10, IFNγ, and IL-6 showed elevation at 2 to 4 hours, peak at 6 to 8 hours, and plateau/partial resolution at 24 hours but, beyond the 540 µg dose, did not show a clear dose-effect relationship. Ten participants experienced dose-limiting toxicities; the recommended phase II dose for intratumoral ulevostinag was 540 µg. In the phase II...