ArticleCancer chemotherapy and pharmacology2025
A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.
Article in Cancer chemotherapy and pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03772925 (A Phase 1 Study of MLN4924), which is not on this map. Cited by 12 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1 Study of MLN4924 (Pevonedistat) and Belinostat in Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
Who cites it
12 citing papers in PubMed.
- Protein neddylation as a therapeutic target: challenges and opportunities.The Journal of clinical investigation · 2026Review
- The circadian architecture of tumor immunity: mechanistic insights and treatment strategies.Biomarker research · 2026Review
- Review
- Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies.Molecules (Basel, Switzerland) · 2026Review
- Molecularly targeted therapy and immunotherapy in leukemias.Journal of hematology & oncology · 2026Review
- Epigenetic Targeting in Myeloid Malignancies.Advances in experimental medicine and biology · 2026Review
- Decoding the ubiquitin network: molecular mechanisms and therapeutic vulnerabilities for precision radio-sensitization in cancer.Molecular cancer · 2025Review
- Histone modifications in cervical cancer: Epigenetic mechanisms, functions and clinical implications (Review).Oncology reports · 2025Review
- Review
- Targeting the epigenetic regulation of ferroptosis: a potential therapeutic approach for sepsis-associated acute kidney injury.Clinical epigenetics · 2025Review
- The Role of the Sirtuin Family Histone Deacetylases in Acute Myeloid Leukemia-A Promising Road Ahead.Cancers · 2025Review
- Ferroptosis: Mechanisms, Comparison with Cuproptosis and Emerging Horizons in Therapeutics.Oncology research · 2025Review
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
purposeRelapsed 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.
methodsEighteen patients (16 with AML, 2 with MDS) were treated at 5 dose levels (belinostat 800-1000 mg/m
resultsNo 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.
conclusionsPatterns 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 registrationClinicalTrials.gov ID NCT03772925, first posted 12/12/2018; CTEP Identifier 10246.
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