Feasibility of pevonedistat combined with azacitidine, fludarabine, cytarabine in pediatric relapsed/refractory AML: Results from COG ADVL1712.
Authors: Tarlock Katherine , Liu Xiaowei , Minard Charles G. , Menig Sarah , Reid Joel M. , Isikwei Emasenyie , Bergeron Sharon , Horton Terzah M , Fox Elizabeth , Weigel Brenda , Cooper Todd Michael 
Published: June 2021

10018 Background: Outcomes for children with relapsed/refractory (R/R) AML and 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, cell growth and survival. In preclinical models, pevonedistat was synergistic with cytarabine (AraC) and azacitidine (aza). The combination of pevonedistat + aza in adults with AML demonstrated improved responses compared to either single agent. We evaluated the feasibility, toxicity and pharmacokinetics (PK) of pevonedistat in combination with aza, fludarabine, AraC (Aza-FLA) in children with R/R AML and MDS. Methods: Pevonedistat 20 mg/m2, IV days 1, 3, 5, the recommended adult dose, was administered in combination with aza (75 mg/m2, days 1-5), fludarabine (30 mg/m2, days 6-10), and AraC (2000 mg/m2, days 6-10). Intrathecal AraC was administered at the start of therapy and additional doses given to patients with CNS leukemia. If < 33% of the initial 6 enrolled patients experienced dose limiting toxicity (DLT) during cycle 1 the regimen would be considered tolerable and 6 additional patients could enroll to further assess tolerability and PK. Pevonedistat PK was determined during cycle 1 following doses 1 and 5. Response was evaluated after cycle 1. Results: A total of 12 patients were enrolled, median age was 13 years (range 1-21). All patients received prior chemotherapy, median number of prior regimens was 2 (range 1-5) and 3 (25%) patients had prior hematopoietic stem cell transplant. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy related AML (n = 1). One of the initial 6 patients had DLTs (hypertension, GGT elevation, and proteinuria); pevonedistat 20 mg/m2 + Aza-FLA was considered tolerable. Six additional patients were enrolled, two had DLTs (weight loss, hypoxia). Overall, 3/12 (25%) of patients experienced DLTs. As expected, using the intensive Aza-FLA backbone, myelosuppression, electrolyte abnormalities, and hepatic transaminase elevation were common. Day 1 PK parameters (n = 12, mean±SD) were: Cmax= 223±91 ng/mL, AUC0-24h= 892±216 ng/hr/mL, T1/2=4.3±1.2 hours, CL = 23.2±6.9 L/hr/m2. PK parameters were similar following doses 1 and 5, for patients < 12 (n = 6) and ≥ 12 (n = 6) years, and to adult PK profiles. Ten patients were evaluable for response. The overall response rate was 30% (95% CI: 7,75) with 3 patients achieving a CR with incomplete hematologic recovery (CRi). Conclusions: Pevonedistat 20 mg/m2 combinedwith Aza-FLA was tolerable in children with R/R AML. The toxicity of the regimen was similar to other intensive AML regimens. PK parameters were similar among the two age groups and were comparable to adults. Within the confines of a phase I study, there was limited anti-leukemic activity of the combination of pevonedistat +Aza-FLA in R/R AML. Clinical trial information: NCT03813147.