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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Swords, RT; Erba, HP; DeAngelo, DJ; Bixby, DL; Altman, JK; Maris, M; Hua, Z; Blakemore, SJ; Faessel, H; Sedarati, F; Dezube, BJ; Giles, FJ; Medeiros, BC

Published Date

  • May 2015

Published In

Volume / Issue

  • 169 / 4

Start / End Page

  • 534 - 543

PubMed ID

  • 25733005

Pubmed Central ID

  • 25733005

Electronic International Standard Serial Number (EISSN)

  • 1365-2141

Digital Object Identifier (DOI)

  • 10.1111/bjh.13323

Language

  • eng

Conference Location

  • England