Background: The novel small molecule CCX559 is a highly potent and selective PD-L1 inhibitor that induces the dimerization and internalization of cell-surface PD-L1. CCX559, when orally administered in animal models, demonstrated anti-tumor efficacy, including the ability to induce complete responses (Li C, et al. Cancer Res 2021;81(13_Suppl): Abstract nr 1274). Safety pharmacology and toxicology studies in animals demonstrated an acceptable safety profile for CCX559. Taken together, the preclinical data supports the initiation of human trials in patients with advanced solid tumors. PD-(L)1 therapies have been shown to increase peripheral T cell activation and cytokines such as IFNγ and CXCL9 in patients (Herbst RS, et al. Nature.2014; 515(7528):563–567). Methods: This phase 1, first-in-patient, multicenter, open-label, dose-escalation study evaluates safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of CCX559 in patients with refractory, locally advanced or metastatic solid tumors. CCX559 is dosed orally once daily with a starting dose level of 30 mg. Dose escalation/de-escalation is based on the Bayesian Optimal Interval (BOIN) design. PBMC and plasma samples were collected from patients over the first 2 cycles (6 weeks) of treatment, and PD assays were performed, including measurement of cytokines and T cell proliferation. Results: As of February 1, 2022, one patient per cohort was enrolled at the 30 mg and 60 mg levels, and 9 patients were enrolled in the 120 mg dose cohort. Of the 11 patients enrolled, 5 patients (all 120 mg cohort) remain on treatment. No DLTs, treatment-related SAEs, or severe (Grade 3 or higher) treatment-related AEs have been reported. PD assays have been performed with samples from the 30 mg (n=1), 60 mg (n=1), and 120 mg (n=3) cohorts. Patients in all three cohorts showed increased peripheral CD4 and CD8 T cell proliferation starting in the first cycle (21 days) of treatment, as measured by Ki67 positivity. Increases in plasma IFNγ, CXCL9, CXCL10, and CXCL11 levels were observed, in particular in one patient (120 mg cohort) starting 15 days after treatment initiation. Conclusions: Initial results from the phase 1 dose-escalation study of CCX559 indicate on-target PD effects consistent with PD-L1 inhibition. Updated PD data, together with the safety and PK profile, will be presented. Clinical trial information: ACTRN12621001342808.