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- Title
Pevonedistat ( MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.
- Authors
Swords, Ronan T.; Erba, Harry P.; DeAngelo, Daniel J.; Bixby, Dale L.; Altman, Jessica K.; Maris, Michael; Hua, Zhaowei; Blakemore, Stephen J.; Faessel, Hélène; Sedarati, Farhad; Dezube, Bruce J.; Giles, Francis J.; Medeiros, Bruno C.
- 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/m2, 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.
- Subjects
ACUTE myeloid leukemia; ENZYME inhibitors; MYELODYSPLASTIC syndromes; PHARMACOKINETICS; PHARMACODYNAMICS; PATIENTS
- Publication
British Journal of Haematology, 2015, Vol 169, Issue 4, p534
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1111/bjh.13323