Pevonedistat and Belinostat Therapy Demonstrates Safety, Modest Activity for Patients With R/R Acute Myeloid Leukemia or High-Risk MDS

Among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), the combination of belinostat and pevonedistat demonstrated some activity and limited toxicity at various dosage levels, according to results published in Cancer Chemotherapy and Pharmacology.

Combination therapy of belinostat plus azacitidine or bortezomib has previously demonstrated efficacy for the treatment of AML and MDS among patients. Inhibited tumor growth has been associated with pevonedistat, a NEDD-8-activating enzyme inhibitor, which combined with belinostat has shown efficacy for AML treatment in xenograft models.

To determine the safety and tolerability of pevonedistat plus belinostat among patients with R/R AML and/or high-risk MDS, researchers conducted a phase 1, multi-center, dose escalation study among 18 patients.The primary outcome was maximum tolerated dose determination or a recommended phase 2 dose. Toxicities, antileukemic activity/responses, pharmacokinetics were secondary objectives.

Among all enrolled patients, 89% of patients had R/R AML and 11% had MDS. Patients were stratified to 5 dose levels, 800-1000 mg of belinostat and 20-50 mg of pevonedistat. Complete response was reached by 1 patient and 4 had stable disease. Adverse events were experienced by 33% of patients, which included a decrease in white blood cell count (22%), neutrophil count (17%), platelet counts (28%), as well as 17% of patients experiencing anemia and 6% neutropenic fever. Treatment discontinuation occurred in 67% of patients.

Pharmacokinetic data revealed no difference at dose level for pevonedistat plus belinostat. Pharmacodynamic testing results demonstrated an increase in proteins including NQO1 and GSR which are associated with oxidative stress, and SLC7A11which is associated with ferroptosis. 

“The results of the present study indicate that a regimen combining the NEDD8 inhibitor pevonedistat with the HDAC inhibitor belinostat is safe and unassociated with DLTs at the dose levels examined,” the researchers concluded, “The PK [pharmacokinetic] and PD [pharmacodynamic] data as presented herein could have important implications for future iterations of this drug combination in AML.”

Source:

Maher KR, Shafer D, Schaar D, et al. A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Cancer Chemotherapy and Pharmacology. Published online January 17, 2025. doi: 10.1007/s00280-024-04742-9.