General AML

Phase Ib study of pevonedistat plus azacitidine in older AML patients

Addition of the first-in-class NEDD8-Activating Enzyme (NAE) inhibitor, pevonedistat (PEV), to azacitidine (AZA) was well tolerated in treatment-naïve Acute Myeloid Leukemia (AML) patients who are 60 years and over and unfit for intensive chemotherapy, according to results from a phase Ib study (NCT01814826) published in Blood on 18 January 2018, by Ronan T. Swords from the Sylvester Comprehensive Cancer Center, Miami, FL, and colleagues.

PEV works by disrupting cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumor cells via the deregulation of S-phase DNA synthesis. In preclinical studies, PEV enhances the anti-leukemic effects of AZA in AML cell lines. In this phase Ib dose-escalation study, Sword et al. aimed to investigate the safety and tolerability of PEV plus AZA in treatment-naïve older AML patients. The primary endpoints of the study were to determine the Dose Limiting Toxicity (DLT) and the Maximum Tolerated Dose (MTD) of PEV in combination with AZA.

In total, 64 AML patients with a median age of 75 years (range, 61 – 89 years) were enrolled in this study. Patients were administered intravenous (IV) PEV at either 20 mg/m2 (n = 6) or 30 mg/m2 (n = 3) on days 1, 3 and 5 plus a fixed dose of AZA (75 mg/m2 IV or subcutaneously) on days 1 – 5, 8 and 9, every 28 days until disease progression or unacceptable toxicity. Patients in the expansion cohort (n = 55) were treated at the MTD.            

Key findings:
  • Safety in all Intention-to-Treat (ITT) patients (n = 64)
    • Median number of cycles of treatment with PEV plus AZA: 4 cycles (range, 1–37)
    • DLT of persistent grade 2 bilirubin elevation and reversible grade 4 AST elevation occurred in two patients respectively receiving PEV at 30 mg/m2
    • MTD of PEV in combination with AZA: 20 mg/m2
    • Most frequent treatment-emergent adverse events include constipation (48%), nausea (42%), fatigue (42%) and anemia (39%)
    • Death occurred in 11 patients due to disease progression or disease-related events but deemed unrelated to study therapy
  • Efficacy
    • Overall Response Rate (ORR) in ITT patients = 50%
      • Median remission duration = 8.3 months
      • 91% of patients achieved responses within the first 2– 4 cycles of treatment
    • Median overall survivals of patients treated at the MTD = 7.0 months

In summary, PEV in combination with AZA led to response rates and durable remissions with limited additional toxicity beyond what is expected for AZA alone.  The authors concluded by noting that, the “timing and frequency of responses suggest potential benefit for the addition of PEV to standard regimen of single agent AZA”.


Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study (NCT01814826) of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naïve AML, unfit for standard induction therapy, received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5, combined with fixed-dose AZA (75 mg/m2 IV/SC) on days 1-5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in AST and ALT were dose limiting. The recommended phase 2 dose of PEV in this combination is 20 mg/m2. PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an ITT analysis was 50% (20 CR, 5 CRi, 7 PR), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR.

  1. Swords R.T. et al. Pevonedistat, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, combined with azacitidine, in patients with AML. Blood. 2018 Jan 18. DOI: 10.1182/blood-2017-09-805895.