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

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.

• Authors: Katherine Tarlock, Xiaowei Liu, Charles G Minard, Emasenyie A Isikwei, Joel M Reid, Terzah M Horton, Elizabeth Fox, Brenda J Weigel, Todd Cooper
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 70 Issue 12 Pg. e30672 (Dec 2023) ISSN: 1545-5017 [Electronic] United States
• PMID: 37710306 (Publication Type: Journal Article)
• Copyright: © 2023 Wiley Periodicals LLC.