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

• Published in: Blood Vol. 131; no. 13; pp. 1415 - 1424
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.03.2018; American Society of Hematology
• Subjects: Aged; Aged, 80 and over; Azacitidine - administration & dosage; Azacitidine - adverse effects; Clinical Trials and Observations; Cyclopentanes - administration & dosage; Cyclopentanes - adverse effects; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Female; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Male; Middle Aged; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Risk Factors; Ubiquitin-Conjugating Enzymes - antagonists & inhibitors; Ubiquitin-Conjugating Enzymes - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2017-09-805895

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 = 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. •RP2D of PEV 20 mg/m2 in PEV/AZA combo did not alter toxicity profile of AZA; dose-limiting toxicities were transiently elevated AST/ALT.•In treatment-naive older AML patients, the intent-to-treat ORR was 50%.