Background: PLX3397 is a novel, oral small molecule that potently and selectively inhibits i) FMS, Kit, and Flt3‑ITD kinases, which regulate key components of the tumor microenvironment (macrophages, microglia, osteoclasts, and mast cells), and ii) oncogenic variants of these kinases that drive certain tumors. Anti-tumor benefits may be achieved via reduced tumor growth, angiogenesis and metastasis, with the potential to confer an overall survival benefit. Methods: This phase I dose escalation study was designed to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of PLX3397 administered by continuous daily oral dosing in four week cycles in sequential cohorts of 3-6 patients (pts) with solid tumors. Results: In 5 dose escalation cohorts, 26 pts with advanced solid tumors were treated with PLX3397 doses of 100-900 mg daily. PK data reveal dose-dependent systemic exposure (R²=0.99) that, based on in vivo pharmacology data, exceeds the EC90 for Fms inhibition. An elimination half-life of 20 hrs enables a once-daily dosing regimen. PLX3397 was generally well tolerated, with drug-attributable toxicities (mostly grade 1) of anemia, fatigue, nausea, and rash. PD biomarkers are consistent with robust target inhibition, including a pronounced reduction in a defined subset of circulating monocytes (CD14^dim/CD16⁺), and at higher PLX3397 systemic concentrations, a marked increase (up to 10-fold) in serum CSF-1, an activating ligand of FMS. A reduction in circulating tumor cells (CTC) has been demonstrated in 3 of 4 pts who had baseline levels ≥ 5 per 7.5 mL blood. These CTC reductions were accompanied by reduced narcotic use (n=2) and skin metastasis inflammation (n=1). Additionally, hair depigmentation has been observed in 4 pts treated at 600 or 900 mg/day, indicating substantial Kit target inhibition. Conclusions: PLX3397 represents a novel therapeutic approach for cancer, showing dose-proportional systemic exposure clearly reaching an efficacious range for both FMS and Kit inhibition. The selectivity of PLX3397 has translated into a favorable safety profile. The first of several planned phase II trials in selected indications has been initiated in refractory Hodgkin lymphoma.