Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.
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.
Leukemia Program, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
Ronan T
RT
Swords
Harry P
HP
Erba
Daniel J
DJ
DeAngelo
Dale L
DL
Bixby
Jessica K
JK
Altman
Michael
M
Maris
Zhaowei
Z
Hua
Stephen J
SJ
Blakemore
Hélène
H
Faessel
Farhad
F
Sedarati
Bruce J
BJ
Dezube
Francis J
FJ
Giles
Bruno C
BC
Medeiros
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood; D003517:Cyclopentanes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000097:blood / Q000139:chemically induced; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors*
D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat
MLN4924; NEDD8; NEDD8-activating enzyme; acute myeloid leukaemia; pevonedistat