Feasibility of Pevonedistat Combined with Azacitidine, Fludarabine, Cytarabine in Pediatric Relapsed/Refractory AML: Results from COG ADVL1712

Authors

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

Publication Date

12-1-2023

Journal

Pediatric Blood & Cancer

DOI

10.1002/pbc.30672

PMID

37710306

PMCID

PMC10864008

PubMedCentral® Posted Date

12-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Adolescent, Adult, Child, Child, Preschool, Humans, Infant, Young Adult, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Chronic Disease, Cyclopentanes, Cytarabine, Feasibility Studies, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Pyrimidines, Vidarabine, AML, Pevonedistat, Relapse

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 2 (range 1-5) and 3 (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, 3/12 (25%) patients experienced DLTs. The day 1 mean±SD (n=12) C_max, V_SS, T_1/2, and CL were 223±91 ng/mL, 104±53.8 L/m², 4.3±1.2 hours, and 23.2±6.9 L/hr/m², respectively. T_1/2, V_SS, and C_max 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.

Comments

Associated Data