Dear Sir, We previously reported the therapeutic potential of pevonedistat (TAK-924/MLN4924), a novel inhibitor of protein neddylation, in patients with acute myeloid leukemia (AML). 1 Pevonedistat is a small-molecule inhibitor of the neural cell developmentally downregulated 8 (NEDD8)-activating enzyme, which processes NEDD8 for binding to target substrates. 2–5 The most characterized NEDD8 target in cells are the Cullin-RING E3 ubiquitin ligases (CRLs), which direct the degradation of specific substrates through the proteasome (for example, p27, CDT1, Nrf-2). 6 In the absence of NEDD8, CRL substrates accumulate causing antiproliferative effects in AML. 1 In a phase I trial (C15003 study), patients with relapsed/refractory myelodysplastic syndrome or AML were treated with 1-h infusions of pevonedistat every 21 or 28 days across five schedules. On Schedule A, dose escalation commenced at 25 mg/m2 on Days 1, 3 and 5 in a standard ‘3+ 3’manner to determine the maimum tolerated dose (MTD). Following this, four additional schedules were evaluated with pevonedistat: Schedule B (Days 1, 4, 8 and 11 starting at 147 mg/m2); Schedule C (Days 1, 8 and 15 starting one dose level lower than the MTD determined for Schedule A (44 mg/m2)); Schedule D (Days 1, 3 and 5 stating at 45 mg/m2 to be combined with azacitidine 75 mg/m2 on Days 1–5 and 8–9); and Schedule E (Days 1, 3 and 5 at fixed dose of 50 mg/m2). Schedules A–C and E were administered every 21 days, whereas schedule D was administered every 28 days. Adverse events (AEs) on Schedules A and B were taken into account when designing Schedules C–E; based on Schedule A MTD, an expansion dose of 50 mg/m2 was selected for Schedule E. Results for Schedules A and B were published by Swords et al., 7 and the reported MTDs were 59 and 83 mg/m2, respectively. Hepatotoxicity was dose limiting for Schedule A and multiorgan failure (MOF) for Schedule B. The objective response rate in patients treated at or below the MTD was 17% for Schedule A and 10% for Schedule B, confirming single agent activity in refractory AML patients. 8 Considering the promising safety and activity of pevonedistat reported thus far, 8–10 we carried out a comprehensive safety analysis of all 72 patients treated across five schedules (A–E) in the C15003 study.

Seventy-two patients were evaluable for toxicity: Schedule A (n= 27), Schedule B (n= 26), Schedule C (n= 2), Schedule D (n= 1), and Schedule E (n= 16). Most patients had AML (N= 66, 92%), 5 had myelodysplastic syndrome (7%) and 1 patient had ALL (1%). Median age was 65.5 years (range: 19–84). The most frequently reported all-grade AEs were: pyrexia (49%), diarrhea (43%), decreased appetite (35%), peripheral edema (33%), dyspnea and fatigue (each 32%), febrile neutropenia (31%) and nausea (31%). These were generally mild and transient. The most common reported laboratory toxicities were elevations in aspartate aminotransferase (25%) and alanine transaminase (24%). Treatment-related myelosuppression was infrequent with thrombocytopenia reported in 18% of patients. Fifteen (21%) patients