Background: Immuno-oncology therapies, including immune checkpoint inhibitors (CPIs), are revolutionizing cancer treatment. However, primary and secondary resistance to CPIs remains a significant challenge. CPI resistance has been associated with reduced interferon (IFN) signaling, altered antigen presentation, and an immunosuppressive tumor phenotype. Stimulating innate immune cells to develop a proinflammatory tumor environment that activates IFN signaling and downstream adaptive antitumor immune mechanisms is predicted to overcome such resistance. Stimulator of Interferon Genes (STING) is a key mediator of type 1 IFN-dependent innate immune modulation. Most STING agonists evaluated clinically have required intratumoral administration, which has significant logistical challenges and excludes many pts whose tumors are not accessible for injection. TAK-676 is a novel STING agonist under clinical investigation as an IV administered systemic therapy in pts with solid tumors. Methods: The primary objective of this study is to determine the safety and tolerability of TAK-676 alone and in combination with pembrolizumab. Secondary objectives are to: determine the pharmacologically active dose and recommended phase 2 dose; characterize TAK-676 pharmacokinetics; assess preliminary antitumor activity; and assess STING agonism gene signature induction. An exploratory objective is to assess immune cell activation and clinical response. The study comprises a single-pt safety lead-in with single-agent (SA) TAK-676 0.1 mg IV, followed by dose escalation using Bayesian Logistic Regression Model design. Dose escalation will start in the combination arm when ≥2 dose levels in the SA arm have been evaluated and considered safe. In both arms, pts will receive TAK-676 on days 1, 8, and 15 in 21-day cycles for up to 1 year. In the combination arm, pts will also receive pembrolizumab 200 mg IV on day 1 of each cycle. Adult pts with histologically confirmed advanced or metastatic solid tumors who have no standard therapeutic options or are intolerant to them, with an Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and ≥1 Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1- evaluable lesion are eligible; pts with tumors that have relapsed, are refractory or naïve to anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) therapy are eligible for the combination arm. Planned enrollment is ̃76 pts; recruitment is ongoing. Clinical trial information: NCT04420884