A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome

Abstract

Purpose: Relapsed and/or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome continue to have a poor prognosis with limited treatment options despite advancements in rational combination and targeted therapies. Belinostat (an HDAC inhibitor) and Pevonedistat (a NEDD8 inhibitor) have each been independently studied in hematologic malignancies and have tolerable safety profiles with limited single-agent activity. Preclinical studies in AML cell lines and primary AML cells show the combination to be highly synergistic, particularly in high-risk phenotypes such as p53 mutant and FLT-3-ITD positive cells. Here, we present the safety, pharmacokinetics and pharmacodynamics of belinostat and pevonedistat in a dose escalation Phase I study in AML and High-Risk MDS.

Methods: Eighteen patients (16 with AML, 2 with MDS) were treated at 5 dose levels (belinostat 800-1000 mg/m², pevonedistat 20-50 mg/m²). Safety and tolerability were assessed according to protocol defined dose limiting toxicities (DLTs). Correlative pharmacokinetic and pharmacodynamic analyses were performed.

Results: No dose limiting toxicities were noted. Most Grade 3 or 4 toxicities were hematologic in nature. The best response was stable disease in four patients, and complete remission in one patient who qualified as an exceptional responder. Pharmakokinetic studies revealed no association between drug exposure and best response. Pharmacodynamic RT-PCR studies demonstrated post-treatment increases in several proteins, including quantitative increases in the oxidative stress protein NQO1, ferroptosis protein SLC7A11, and GSR, linked to glutathione metabolism and oxidative stress, as did the anti-oxidants SRXN1 and TXNRD1.

Conclusions: Patterns of post-treatment changes in correlative pharmacodynamic parameters may suggest possible mechanistic changes in the DNA damage response, oxidative damage, and ferroptosis pathways. The combination of pevonedistat plus belinosat is safe in an adult relapsed and/or refractory AML/High-Risk MDS population with modest but notable activity in this heavily treated, high risk population. Our findings also raise the possibility that certain extremely poor prognosis AML patients may respond to a regimen combining two targeted agents that have little or no activity when administered individually.

Trial registration: ClinicalTrials.gov ID NCT03772925, first posted 12/12/2018; CTEP Identifier 10246.

Keywords: Acute myeloid leukemia; Belinostat; Myelodysplastic syndrome; Pevonedistat.

Fig. 1

Flow cytometry analysis of pre- and post-treatment patient samples. Peripheral blood mononuclear cells (PBMNCs) were isolated at baseline (Pre) and 24 h after treatment (Post). PBMNCs for each sample were analyzed for levels of CtIP, Cdt-1, BIM, Ac-H4K16, p-Wee1, BCL-2, BCL-xL, MCL-1, p-FANCD2, p-Chk1 and gH2AX. Analysis of biomarkers were performed on the CD45^dim SS^low CD3- CD20- population. The Mean fluorescence Intensity (MFI) ratios of biomarker signals to their isocontrols for pre-treatment samples for each patient was set as 100%. Analysis for each individual biomarker is represented as a bar chart showing the relative level of the assayed protein in samples after averaging, including standard deviation bars. The Student t test was performed to indicate the significance of changes in post versus pre-treatment samples

Fig. 2

RT-PCR analysis of pre- and post-treatment patient samples. RNA was isolated from cells at baseline (Pre) and 6 h after treatment (Post). RT-qPCR analysis was performed to determine the relative expression levels of NQO1, SLCA11, ATF3, GCLM, GSR, MAG1, SRXN1 and TXNRD1. The expression of each gene was normalized to the average expression levels of the 4 endogenous reference genes e.g., 18S, B2M, RPLP0 and UBC. Analysis of each individual biomarker is shown as a bar chart illustrating the relative level of the assayed target gene, including standard deviation bars. The Student t test was performed to show the significance of post- versus pre-treatment changes