UNASSIGNED: 3093 Background: @entity6827 is a novel, oral small molecule that potently and selectively inhibits i) FMS, Kit, and @entity7801 -ITD kinases, which regulate key components of the @entity5 microenvironment (macrophages, microglia, osteoclasts, and mast cells), and ii) oncogenic variants of these kinases that drive certain @entity5 . Anti- @entity5 benefits may be achieved via reduced @entity5 growth, angiogenesis and @entity3 , 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 @entity6827 administered by continuous daily oral dosing in four week cycles in sequential cohorts of 3-6 @entity1 (pts) with solid @entity5 . RESULTS: In 5 dose escalation cohorts, 26 pts with advanced solid @entity5 were treated with @entity6827 doses of 100-900 mg daily. PK data reveal dose-dependent systemic exposure (R(2)=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. @entity6827 was generally well tolerated, with drug-attributable @entity137 (mostly grade 1) of @entity417 , @entity1295 , @entity390 , and @entity1910 . PD biomarkers are consistent with robust target inhibition, including a pronounced reduction in a defined subset of circulating monocytes ( @entity5750 (dim)/ @entity4071 (+)), and at higher @entity6827 systemic concentrations, a marked increase (up to 10-fold) in serum @entity6824 , an activating ligand of FMS. A reduction in circulating @entity5 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 @entity3 @entity32 (n=1). Additionally, hair depigmentation has been observed in 4 pts treated at 600 or 900 mg/day, indicating substantial Kit target inhibition. CONCLUSIONS: @entity6827 represents a novel therapeutic approach for @entity5 , showing dose-proportional systemic exposure clearly reaching an efficacious range for both FMS and Kit inhibition. The selectivity of @entity6827 has translated into a favorable safety profile. The first of several planned phase II trials in selected indications has been initiated in refractory @entity978 .

Pharmacodynamic activity demonstrated in phase I for XXXX , a selective inhibitor of FMS and Kit.

@entity1 :: ('9606', 'Species') :: ['patients'] @entity32 :: ('MESH:D007249', 'Disease') :: ['inflammation'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicities'] @entity390 :: ('MESH:D009325', 'Disease') :: ['nausea'] @entity417 :: ('MESH:D000740', 'Disease') :: ['anemia'] @entity1910 :: ('MESH:D005076', 'Disease') :: ['rash'] @entity6827 :: ('MESH:C000600259', 'Chemical') :: ['PLX3397'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'cancer', 'tumors'] @entity5750 :: ('929', 'Gene') :: ['CD14'] @entity1295 :: ('MESH:D005221', 'Disease') :: ['fatigue'] @entity7801 :: ('2322', 'Gene') :: ['Flt3'] @entity4071 :: ('2214', 'Gene') :: ['CD16'] @entity3 :: ('MESH:D009362', 'Disease') :: ['metastasis'] @entity6824 :: ('1435', 'Gene') :: ['CSF-1'] @entity978 :: ('MESH:D006689', 'Disease') :: ['Hodgkin lymphoma']
@entity6827 :: (MESH:C000600259,Chemical) :: ['PLX3397']
