Background: MLN4924 is an investigational small molecule NAE inhibitor; NAE controls the NEDD8 conjugation pathway and regulates cullin-RING ligase (CRL) activity. MLN4924 has antitumor activity in preclinical models of several tumor types. The MTD of MLN4924 on d 1–5 of 21-d cycles (schedule A) is 50 mg/m². Two other schedules are being investigated with the aim of further dose escalation. Methods: Pts received 1-hr IV infusions of MLN4924 on d 1, 3, and 5 of 21-d cycles, with (schedule B) or without (schedule C) dexamethasone 8 mg prior to MLN4924 and on d 1, 3, and 5. Dose-escalation proceeded via a Bayesian continual reassessment method. Blood samples were collected in cycle 1 for PK analysis. Results: On schedules B and C, respectively, 17 and 16 pts were enrolled to 50 (n=12, 2), 67 (n=3, 10), or 89 (n=2, 4) mg/m². Median age was 60.8 yrs; 58% were male. Diagnoses included colorectal cancer (CRC; 28%), melanoma (19%), and gastric cancer (13%). Pts on schedules B and C had a median of 3 and 1.5 cycles, respectively. Schedule B DLTs were elevated ALT at 50 mg/m² and hyperbilirubinemia at 67 and 89 mg/m²; schedule C DLTs were hyperbilirubinemia and AST elevation at 89 mg/m². Schedule B and C MTDs were 50 and 67 mg/m², respectively. Common AEs on schedule B were fatigue (47%), hyperbilirubinemia, elevated ALT, constipation, and anorexia (each 24%) and on schedule C were anemia, nausea (each 44%), hypocalcemia (38%), hypomagnesemia, myalgia, and hyponatremia (each 25%); grade ≥3 AEs were seen in 35% and 44% of pts, respectively. Six pts on schedule B (3 melanoma, 1 CRC, 1 head and neck, 1 SCLC) and 3 on schedule C (all CRC) had SD durable for ≥4 cycles. Preliminary MLN4924 PK profiles were similar on d 1 and 5, suggesting no apparent accumulation in plasma. Single-dose dex prior to MLN4924 did not appear to decrease MLN4924 plasma exposure. In cycle 1 MLN4924 was shown to exert predicted pharmacodynamic effects in tumor/non-tumor tissues (blood, skin), e.g. upregulation of CRL substrate Cdt-1 in tumor tissue, consistent with NAE inhibition. Conclusions: MLN4924 was generally well tolerated at the dosing schedules studied, with evidence of target inhibition and antitumor activity.