2562 Background: MLN4924 is a first-in-class, small molecule inhibitor of NEDD8 Activating Enzyme (NAE) with potent antitumor activity in animal models. Inhibition of NAE by MLN4924 leads to decreased neddylation and inhibition of cullin-RING ubiquitin ligase (CRL) activity. CRLs are enzyme complexes that control the ubiquitination and degradation of proteins with important roles in cell cycle and survival. Potent antitumor activity in animal models correlates with accumulation of substrates of the CRLs associated with DNA replication (e.g.Cdt-1), stress response (e.g.Nrf-2), and signal transduction (e.g. pIκB). Methods: A primary objective of this phase I trial in patients (pts) with advanced non-hematologic malignancies was to evaluate the pharmacodynamic (PD) effects of MLN4924 as measured by accumulation of pIκB in peripheral blood mononuclear cells (PBMCs) and Cdt-1 and Nrf-2 in skin. Pts were treated with a daily infusion of MLN4924 for 5 days of a 21-day cycle. PBMCs were isolated for analysis of pIκB levels at screening, baseline, and at selected time points following its administration. Skin biopsies for assay of Cdt-1 and Nrf-2 were performed at baseline and following the second dose of MLN4924. Results: 10 pts have been treated at 3 dose levels. Treatment emergent adverse events include elevations in transaminases, bilirubin and alkaline phosphatase. PK analysis indicated approximately dose-proportional increases in MLN4924 exposure with an estimated half life of 5 to 15 hours and no readily apparent drug accumulation. Analysis of pIκB levels in PBMCs demonstrated accumulation from baseline levels following administration of MLN4924. Cdt-1 and Nrf-2 levels in skin rose above baseline following the second dose of MLN4924. Conclusions: Treatment of pts with MLN4924 results in accumulation of substrates associated with inhibition of NAE in both peripheral blood and skin. Inhibition occurs at exposure levels that are comparable to those resulting in pharmacodynamic activity and in vivo tumor activity in xenograft models. Evidence of PD modulation of NAE activity through the accumulation of CRL substrates has been established in this early analysis, and dose escalation is ongoing to establish the MTD of this agent. [Table: see text]