Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML

Ronan T Swords, Steven Coutre, Michael B. Maris, Joshua F. Zeidner, James M. Foran, Jose Cruz, Harry P. Erba, Jesus G. Berdeja, Wayne Tam, Saran Vardhanabhuti, Iwona Pawlikowska-Dobler, Hélène M. Faessel, Ajeeta B. Dash, Farhad Sedarati, Bruce J. Dezube, Douglas V. Faller, Michael R. Savona

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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 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-naive 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/ subcutaneously) on days 1 to 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 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) 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 intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ‡6 cycles of therapy (n 5 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. This study was registered at www.clinicaltrials.gov as #NCT01814826.

Original languageEnglish (US)
Pages (from-to)1415-1424
Number of pages10
JournalBlood
Volume131
Issue number13
DOIs
StatePublished - Mar 29 2018
Externally publishedYes

Fingerprint

Azacitidine
Enzyme Inhibitors
Acute Myeloid Leukemia
Pharmacokinetics
Aspartate Aminotransferases
Alanine Transaminase
Refractory materials
Bone
Therapeutics
Fatigue of materials
Recovery
Constipation
Cytogenetics
Nausea
Composite materials
Fatigue
Enzymes
Anemia
Bone Marrow
Research Personnel

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Swords, R. T., Coutre, S., Maris, M. B., Zeidner, J. F., Foran, J. M., Cruz, J., ... Savona, M. R. (2018). Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood, 131(13), 1415-1424. https://doi.org/10.1182/blood-2017-09-805895

Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. / Swords, Ronan T; Coutre, Steven; Maris, Michael B.; Zeidner, Joshua F.; Foran, James M.; Cruz, Jose; Erba, Harry P.; Berdeja, Jesus G.; Tam, Wayne; Vardhanabhuti, Saran; Pawlikowska-Dobler, Iwona; Faessel, Hélène M.; Dash, Ajeeta B.; Sedarati, Farhad; Dezube, Bruce J.; Faller, Douglas V.; Savona, Michael R.

In: Blood, Vol. 131, No. 13, 29.03.2018, p. 1415-1424.

Research output: Contribution to journalArticle

Swords, RT, Coutre, S, Maris, MB, Zeidner, JF, Foran, JM, Cruz, J, Erba, HP, Berdeja, JG, Tam, W, Vardhanabhuti, S, Pawlikowska-Dobler, I, Faessel, HM, Dash, AB, Sedarati, F, Dezube, BJ, Faller, DV & Savona, MR 2018, 'Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML', Blood, vol. 131, no. 13, pp. 1415-1424. https://doi.org/10.1182/blood-2017-09-805895
Swords, Ronan T ; Coutre, Steven ; Maris, Michael B. ; Zeidner, Joshua F. ; Foran, James M. ; Cruz, Jose ; Erba, Harry P. ; Berdeja, Jesus G. ; Tam, Wayne ; Vardhanabhuti, Saran ; Pawlikowska-Dobler, Iwona ; Faessel, Hélène M. ; Dash, Ajeeta B. ; Sedarati, Farhad ; Dezube, Bruce J. ; Faller, Douglas V. ; Savona, Michael R. / Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. In: Blood. 2018 ; Vol. 131, No. 13. pp. 1415-1424.
@article{25730f5622ca485ba0c652bc87f2c8c3,
title = "Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML",
abstract = "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 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-naive 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/ subcutaneously) on days 1 to 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 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) 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 intent-to-treat analysis was 50{\%} (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ‡6 cycles of therapy (n 5 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. This study was registered at www.clinicaltrials.gov as #NCT01814826.",
author = "Swords, {Ronan T} and Steven Coutre and Maris, {Michael B.} and Zeidner, {Joshua F.} and Foran, {James M.} and Jose Cruz and Erba, {Harry P.} and Berdeja, {Jesus G.} and Wayne Tam and Saran Vardhanabhuti and Iwona Pawlikowska-Dobler and Faessel, {H{\'e}l{\`e}ne M.} and Dash, {Ajeeta B.} and Farhad Sedarati and Dezube, {Bruce J.} and Faller, {Douglas V.} and Savona, {Michael R.}",
year = "2018",
month = "3",
day = "29",
doi = "10.1182/blood-2017-09-805895",
language = "English (US)",
volume = "131",
pages = "1415--1424",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "13",

}

TY - JOUR

T1 - Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML

AU - Swords, Ronan T

AU - Coutre, Steven

AU - Maris, Michael B.

AU - Zeidner, Joshua F.

AU - Foran, James M.

AU - Cruz, Jose

AU - Erba, Harry P.

AU - Berdeja, Jesus G.

AU - Tam, Wayne

AU - Vardhanabhuti, Saran

AU - Pawlikowska-Dobler, Iwona

AU - Faessel, Hélène M.

AU - Dash, Ajeeta B.

AU - Sedarati, Farhad

AU - Dezube, Bruce J.

AU - Faller, Douglas V.

AU - Savona, Michael R.

PY - 2018/3/29

Y1 - 2018/3/29

N2 - 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 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-naive 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/ subcutaneously) on days 1 to 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 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) 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 intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ‡6 cycles of therapy (n 5 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. This study was registered at www.clinicaltrials.gov as #NCT01814826.

AB - 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 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-naive 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/ subcutaneously) on days 1 to 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 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) 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 intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ‡6 cycles of therapy (n 5 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. This study was registered at www.clinicaltrials.gov as #NCT01814826.

UR - http://www.scopus.com/inward/record.url?scp=85047614601&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047614601&partnerID=8YFLogxK

U2 - 10.1182/blood-2017-09-805895

DO - 10.1182/blood-2017-09-805895

M3 - Article

AN - SCOPUS:85047614601

VL - 131

SP - 1415

EP - 1424

JO - Blood

JF - Blood

SN - 0006-4971

IS - 13

ER -