Feasibility of pevonedistat combined with azacitidine, fludarabine, cytarabine in pediatric relapsed/refractory AML: Results from COG ADVL1712

Katherine Tarlock, Xiaowei Liu, Charles G. Minard, Emasenyie A. Isikwei, Joel M. Reid, Terzah M. Horton, Elizabeth Fox, Brenda J. Weigel, Todd Cooper

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1 Scopus citations

Abstract

Background: Outcomes for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor, and new therapies are needed. Pevonedistat is an inhibitor of the NEDD-8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, with protein degradation regulating cell growth and survival. Procedure: We evaluated the feasibility, toxicity, and pharmacokinetics (PK) of pevonedistat (20 mg/m2 days 1, 3, 5) in combination with azacitidine, fludarabine, cytarabine (aza-FLA) in children with R/R AML and MDS (NCT03813147). Twelve patients were enrolled, median age was 13 years (range 1–21). Median number of prior chemotherapeutic regimens was two (range one to five), and two (25%) patients had prior hematopoietic cell transplantation. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy-related AML (n = 1). Results: Overall, three of 12 (25%) patients experienced DLTs. The day 1 mean ± SD (n = 12) Cmax, VSS, T1/2, and CL were 223 ± 91 ng/mL, 104 ± 53.8 L/m2, 4.3 ± 1.2 hours, and 23.2 ± 6.9 L/h/m2, respectively. T1/2, VSS, and Cmax, but not CL, were significantly different between age groups. The overall response rate was 25%, with n = 3 patients achieving a complete remission with incomplete hematologic recovery (CRi). Conclusions: Pevonedistat 20 mg/m2 combined with Aza-FLA was tolerable in children with R/R AML with similar toxicity profile to other intensive AML regimens. However, within the confines of a phase 1 study, we did not observe that the pevonedistat + Aza-FLA combination demonstrated significant anti-leukemic activity.

Original languageEnglish (US)
Article numbere30672
JournalPediatric Blood and Cancer
Volume70
Issue number12
DOIs
StatePublished - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023 Wiley Periodicals LLC.

Keywords

  • AML
  • pevonedistat
  • relapse

PubMed: MeSH publication types

  • Clinical Trial, Phase I
  • Journal Article

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