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.
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Embargo End Date
2026-06-10
ICR Authors
Authors
Harrington, KJ
Champiat, S
Brody, JD
Cho, BC
Romano, E
Golan, T
Hyngstrom, JR
Strauss, J
Oh, DY
Popovtzer, A
Gomez-Roca, C
Perets, R
Kim, S-B
Wong, DJ
Powell, SF
Khilnani, A
Jemielita, T
Zhao, Q
Zhao, R
Ingham, M
Champiat, S
Brody, JD
Cho, BC
Romano, E
Golan, T
Hyngstrom, JR
Strauss, J
Oh, DY
Popovtzer, A
Gomez-Roca, C
Perets, R
Kim, S-B
Wong, DJ
Powell, SF
Khilnani, A
Jemielita, T
Zhao, Q
Zhao, R
Ingham, M
Document Type
Journal Article
Date
2025-08-14
Date Accepted
2025-06-09
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.
Citation
Clinical Cancer Research, 2025, 31 (16), pp. 3400 - 3411
Source Title
Clinical Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Targeted Therapy