Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study

Br J Haematol. 2015 May;169(4):534-43. doi: 10.1111/bjh.13323. Epub 2015 Mar 2.

Abstract

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

Trial registration: ClinicalTrials.gov NCT00911066.

Keywords: MLN4924; NEDD8; NEDD8-activating enzyme; acute myeloid leukaemia; pevonedistat.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Chemical and Drug Induced Liver Injury / blood
  • Cyclopentanes* / administration & dosage
  • Cyclopentanes* / adverse effects
  • Cyclopentanes* / pharmacokinetics
  • Enzyme Inhibitors* / administration & dosage
  • Enzyme Inhibitors* / adverse effects
  • Enzyme Inhibitors* / pharmacokinetics
  • Female
  • Humans
  • Leukemia, Myeloid, Acute* / blood
  • Leukemia, Myeloid, Acute* / drug therapy
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Multiple Organ Failure / blood
  • Multiple Organ Failure / chemically induced
  • Myelodysplastic Syndromes* / blood
  • Myelodysplastic Syndromes* / drug therapy
  • Pyrimidines* / administration & dosage
  • Pyrimidines* / adverse effects
  • Pyrimidines* / pharmacokinetics
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors*

Substances

  • Cyclopentanes
  • Enzyme Inhibitors
  • Pyrimidines
  • Ubiquitin-Activating Enzymes
  • NAE protein, human
  • pevonedistat

Associated data

  • ClinicalTrials.gov/NCT00911066