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 = 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.

Conflict of interest statement

Conflict-of-interest disclosure: R.T.S. is a consultant for Novartis and receives research funding from Millennium. S.C. is a consultant for Janssen, Pharmacylics, and AbbVie and receives research funding from AbbVie. J.F.Z. receives honoraria from Agios, Celgene, and Tolero and research funding from Merck and Millennium. J.M.F. receives honoraria from Novartis, Pfizer, Karyopharm, and Medscape and research funding from Millennium. J.C. is on the Millennium speakers bureau and receives honoraria from Millennium. H.P.E. is a consultant for Novartis, Celgene, Seattle Genetics, Amgen, Daiichi Sankyo, Sunesis, Janssen, Ariad, and Pfizer; on the data safety and monitoring board at Incyte and Gylcomimetics; on the speakers bureau at Incyte and Celgene; and receives research funding from Seattle Genetics, Amgen, Daiichi Sankyo, Janssen, Celator, Millennium, Astellas, Agios, and Juno. W.T. is a consultant for Millennium. S.V., I.P.-D., H.M.F., A.B.D., F.S., B.J.D., and D.V.F. are Millennium employees. M.R.S. is a consultant for and receives research funding from Astex, Incyte, Millennium, Sunesis, and TG Therapeutics; is on the data safety and monitoring board at Celgene and Gilead; and is a consultant for and has equity in Karyopharm. J.G.B. and M.B.M. declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Figure 1.

Mean (standard deviation) PK profile after 1-hour IV infusion of PEV in combination with AZA in elderly patients with treatment-naive AML. *Derived from single-agent PEV data in patients with AML.

Figure 2.

Duration of response. Bar length reflects duration of response. End of duration is due to progressive disease (PD), last disease assessment, or last follow-up. Gray triangles indicate the 10 patients who did not have postbaseline disease assessment and are listed as not evaluable (NE) but included as “nonresponders” in the ITT analysis. SD, stable disease.

Figure 3.

Kaplan-Meier survival analyses in the MTD cohort. (A) OS of patients treated at the MTD, including the 9 response-unevaluable patients. (B) OS of de novo AML vs secondary AML patients.

Figure 4.

Heatmap showing mutational status of 12 frequently mutated genes and response data for patients in the MTD cohort. Genetic mutation data for 33 of 61 patients identified using a targeted NGS panel are shown. Each column represents a single patient, and each row represents a single gene. Presence of a mutation in any gene is denoted in red. Mutation frequency = (number of patients with mutation/number of NGS-evaluable patients) × 100. In this figure, responders = CR + CRi + PR.