Abstract CT191: Intravenous infusion of the allosteric small molecule STING agonist CRD3874-SI in patients with relapsed or refractory acute myeloid leukemia: A phase I trial

Abstract Background: Treatment for acute myeloid leukemia (AML) relapsed after or refractory to (R/R) standard therapies is an unmet clinical need. Efficacy of immunotherapies is being explored. Stimulator of Interferon Genes (STING) is an important component of the human innate immune system which generates a rapid initial inflammatory response to danger signals associated with cellular or tissue damage from pathogens, via effectors such as cytokines and chemokines. Cytosolic DNA is a danger signal that binds to the enzyme cGAS, generating cyclic dinucleotides (CDNs) that trigger the cGAS-STING pathway, leading to activation of the downstream transcription factors IRF3 and NFκB to induce pro-inflammatory Type I interferons and related cytokines. CDN site-targeting STING agonists tested in the clinic thus far have shown limited systemic tolerability and efficacy. CRD3874 is an allosteric, non-cytotoxic, small-molecule human STING agonist with a unique binding mode that generates robust Type I interferon responses while simultaneously blocking STING proton transport activity associated with pyroptosis and autophagy. The compound has demonstrated impressive tumor clearance in a range of pre-clinical models and high levels of systemic safety in non-human primates. Methods: (Pre-clinical) Allosteric binding was established using radioligand binding assays. Anti-cancer activity of CRD3874-SI by the intravenous (IV) route was evaluated in human STING knock-in (KI) C57BL/6 mice (genOway, Lyon, France). Inflammasome and autophagy markers were studied in human and mouse cells. (Clinical) Patients with R/R AML are eligible for a Phase 1 clinical trial testing CRD3874-SI administered IV at six sequential dose levels, using a 3+3 design, with pharmacokinetic and pharmacodynamic correlative studies at the University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland (NCT06626633). Citation Format: Maria R. Baer, Vu H. Duong, Oyinkansola Arasanmi, Devon T. Issac, Sunita Philip, Megan Wagner, Ar'Lena Hassan, Feyruz V. Rassool, Sandip Middya, Ritesh Shrivastava, Anindita Middya, Nagaswamy Mane, Thanilsana Soram, Kavita Puniya, Nidhi Rawat, Debjani Chakraborty, Rubeena R. Mansuri, Anul Singh, Rajib Ghosh, Anuj Gautam, Sourav Basu, Monali Banerjee, Arjun Surya. Intravenous infusion of the allosteric small molecule STING agonist CRD3874-SI in patients with relapsed or refractory acute myeloid leukemia: A phase I trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT191.