Data from 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
Year: 2025
Type: other
Abstract: 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 study (NCT04220866), 4 of 8 participants treated with combination therapy and 1 of 10 treated with pembrolizumab monotherapy had a complete or partial response. The most common adverse event was pyrexia (n = 5). Conclusions: Intratumoral ulevostinag (±pembrolizumab) had manageable toxicity, dose-dependent pharmacokinetics, and evidence of STING activation and target engagement. Combination therapy showed antitumor activity in participants with untreated metastatic or unresectable, recurrent HNSCC.
Authors: Kevin J. Harrington, Stephane Champiat, Joshua D. Brody, Byoung Chul Cho, Emanuela Romano, Talia Golan, John R. Hyngstrom, James Strauss, David Y. Oh, Aron Popovtzer, Carlos Gomez-Roca, Ruth Perets, Sung-Bae Kim, Deborah J. Wong, Steven F. Powell, Anuradha Khilnani, Thomas Jemielita, Qing Zhao, Runchen Zhao, Matthew Ingham
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W7128210127