Background: Tumor-associated macrophages (TAMs) support tumor growth and cause tumor resistance to chemotherapy and radiation therapy, and myeloid-derived suppressor cells (MDSCs) suppress anti-tumor immunity and cause resistance to PD-1 inhibition. TAMs and MDSCs are both regulated in part by colony stimulating factor 1 (CSF1), which signals via its receptor (CSF1R). Pexidartinib is an orally administered, small molecule inhibitor of the CSF1R. The normal function of PD-1, expressed on the cell surface of activated T-cells, is to suppress excessive immune responses such as autoimmune reactions. Tumors can utilize PD-1 signaling to downregulate immune-mediated elimination. Pembrolizumab is a potent and highly selective humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. We present the study design for an ongoing Phase 1/2a clinical trial assessing the safety, efficacy, pharmacokinetics, and pharmacodynamics of the pexidartinib/pembrolizumab combination in advanced, solid tumors (NCT02452424). Methods: In Part 1 of this open-label, uncontrolled study, patients with advanced solid tumors will be treated with pembrolizumab (200 mg intravenously every 3 weeks) and escalating daily oral doses of pexidartinib to determine the safety and tolerability as well as establish a recommended phase 2 dose (RP2D) for the combination regimen. In Part 2, the combination RP2D will be studied in an expanded panel of solid tumor cohorts in up to 508 patients to further determine safety and preliminary efficacy. Overall response rate (ORR) and progression free survival (PFS) will be evaluated using RECISTv1.1 criteria. Exploratory objectives include identifying biomarkers of clinical activity and drug mechanisms of action. A truncated sequential probability ratio test will be employed in each tumor cohort to allow early decision-making for futility or success. The results will support further development of the pexidartinib/pembrolizumab combination in the solid tumor subtypes that respond to treatment in this study. Clinical trial information: NCT02452424