PURPOSE: This phase I study assessed the safety, pharmacokinetics, and efficacy of MIW815 (ADU-S100), a novel synthetic cyclic dinucleotide that activates the stimulator of interferon genes (STING) pathway, in patients with advanced/metastatic cancers. EXPERIMENTAL DESIGN: Patients (n = 47) received weekly intratumoral injections of MIW815, 50-6400 _g, 3-weeks-on/1-week-off. RESULTS: A maximum tolerated dose was not reached. Most common treatment-related adverse events were pyrexia (17%), chills, and injection site pain (15%). MIW815 was rapidly absorbed from the injection site with dose-proportional pharmacokinetics, a rapid terminal plasma half-life (~24 minutes) and high interindividual variability. One patient had a partial response (Merkel cell carcinoma); two patients had unconfirmed partial responses (parotid cancer; myxofibrosarcoma). Lesion size was stable or decreased in 94% of evaluable, injected lesions. RNA expression and immune infiltration assessments in paired tumor biopsies did not reveal significant on-treatment changes. However, increases in inflammatory cytokines and peripheral blood T-cell clonal expansion suggested systemic immune activation. CONCLUSIONS: MIW815 was well tolerated in patients with advanced/metastatic cancers. Clinical activity of single-agent MIW815 was limited in this first-in-human study, however, evidence of systemic immune activation was seen.