Pevonedistat and Belinostat in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

A Phase 1 Study of MLN4924 (Pevonedistat) and Belinostat in Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

This phase I trial studies side effects and best dose of pevonedistat and belinostat in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (relapsed) or does not respond to treatment (refractory). Chemotherapy drugs, such as pevonedistat and belinostat, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Study Overview

• Status: Terminated
• Conditions: Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic Syndrome; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Pevonedistat; Drug: Belinostat

Detailed Description

PRIMARY OBJECTIVE:

I. To identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for a regimen combining MLN4924 (pevonedistat) with belinostat in patients with refractory/relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

SECONDARY OBJECTIVES:

I. To describe the toxicities of this regimen. II. To observe and record anti-tumor activity. III. If responses are observed, to determine what relationship, if any, exists between such responses and TP53/FLT3 mutational status.

IV. To describe pharmacokinetic (PK) interactions, if any, between MLN4924 (pevonedistat) and belinostat.

V. To test the feasibility of performing correlative studies involving nuclear RelA, phosphorylated (p)-ATR, p-Chk1, Cdt-1, gammaH2A.X, p-HH3, ClCasp3, NQO1, SLC7A11, ATF3, B2M, GCLM, GSR, MAG1, RPLP0, SRXN1, TXNRD1, UBC, p-BRCA1, p-FANCD2, Ac-H3K56, Ac-H4K16, p-Wee1, CtIP, BCL-2, BIM, BCL-xL, or MCL-1.

OUTLINE: This is a dose-escalation study.

Patients receive belinostat intravenously (IV) daily over 30 minutes on days 1-5 and pevonedistat IV once daily (QD) over 60 minutes on days 1, 3, and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 2 months for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
    • Tampa, Florida, United States, 33607
      • Moffitt Cancer Center-International Plaza
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center - McKinley Campus
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have one of the following, histologically or cytologically confirmed:

  • AML (non- acute promyelocytic leukemia [APL] AML)

    • AML that is relapsed or refractory to at least one prior line of therapy

  • MDS, must meet all of the following at the time of enrollment:

    • Higher risk MDS (intermediate-2 or high risk by the original International Prognostic Scoring System [IPSS]), and
    • Relapsed, refractory, or intolerant to at least one prior line of therapy containing a hypomethylating agent (deoxyribonucleic acid [DNA] methyltransferase inhibitor)
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Total bilirubin =< upper limit of normal (ULN) for the laboratory except in patients with Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin =< 1.5 x ULN for the laboratory of the direct bilirubin
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
• Creatinine clearance within normal limits for the laboratory OR estimated glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 appropriate to race for patients with creatinine levels above institutional normal

• Known human immunodeficiency virus (HIV) positive patients who meet the following criteria will be considered eligible:

  • CD4 count > 350 cells/mm^3
  • Undetectable viral load
  • Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents
  • No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy, if indicated
• If history of hepatitis C virus (HCV) infection, patients must be treated and have an undetectable HCV viral load
• The effects of belinostat and/or MLN4924 (pevonedistat) on the developing human fetus are unknown. For this reason and because histone deacetylase inhibitors and NEDD8-activating enzyme (NAE) inhibitory agents are known to be teratogenic, women of child-bearing potential and men must use 1 highly effective method and 1 additional (barrier) method of contraception at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MLN4924 (pevonedistat) and belinostat administration
• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

• Clinical picture indicative of leukostasis or evidence of disseminated intravascular coagulopathy
• Patients with uncontrolled coagulopathy or bleeding disorder
• Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug, except for hydroxyurea
• Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg)
• Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)
• Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)
• Ongoing toxicities >= grade 2 from prior therapy, except those related to hydroxyurea (which is permitted through the first 5 days of study treatment)
• APL (M3)
• Active central nervous system (CNS) leukemia
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN4924 (pevonedistat) or belinostat
• Stem cell transplant within previous 3 months prior to initiation of study therapy
• Major surgical procedures =< 28 days before beginning study treatment or minor surgical procedures =< 7 days before beginning study treatment. No waiting required after placement of a vascular access device
• Uncontrolled intercurrent illness or infection
• Circulating blast count > 50,000 mm^3 within 7 days preceding enrollment
• Current candidacy for a potentially curative allogeneic stem cell transplant, unless declined
• Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or radionuclide angiography

• Prolongation of the heart-rate corrected QT (QTc) interval >= 450 ms (i.e., grade 1 or higher) on electrocardiogram (ECG) prior to initiation of study treatment.

  • If baseline QTc on screening ECG is >= 450 ms (i.e., grade 1 or higher):

    • Check potassium and magnesium serum levels, and
    • Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to confirm QTc interval

  • For patients with baseline heart rate < 60 beats per minute (bpm) or > 100 bpm, manual measurement of QT interval by cardiologist is required, with Fridericia correction applied to that manual measurement to determine the QTc for eligibility consideration

    • Note: For patients with a heart rate of 60-100 bpm, manual measurement of QT interval and use of the Fridericia formula to determine QTc is NOT required

• Known cardiopulmonary disease defined as:

  • Unstable angina
  • Congestive heart failure (New York Heart Association [NYHA] class III or IV)
  • Myocardial infarction (MI) within 6 months prior to first dose (patients who had ischemic heart disease such as acute chest syndrome [ACS], MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll)
  • Symptomatic cardiomyopathy
  • Clinically significant pulmonary hypertension requiring pharmacologic therapy

  • Clinically significant arrhythmia defined as any of the following:

    • History of polymorphic ventricular fibrillation or torsade de pointes
    • Permanent atrial fibrillation (a fib), defined as continuous a fib for >= 6 months
    • Persistent a fib, defined as sustaining a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening
    • Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g., pace maker), or ablation in the past 6 months
    • Patients with paroxysmal a fib or < grade 3 a fib for a period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen
    • Known congenital long QT syndrome
    • Second degree atrioventricular (AV) block type II or third degree AV block
    • Ventricular rate < 50 bpm or > 120 bpm

• Treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of the study drug.

  • Note: Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Ongoing or planned treatment with strong inhibitors of UGT1A1
• Any known UGT1A polymorphism, heterozygous or homozygous
• History of prior therapy with belinostat or MLN4924 (pevonedistat)
• Active gastrointestinal (GI) conditions that might predispose to drug intolerance or poor drug absorption
• Known hepatic cirrhosis
• Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis

• No other prior malignancy is allowed except for the following:

  • In situ cervical cancer,
  • Adequately treated basal cell or squamous cell skin cancer,
  • Adequately treated stage I or II cancer from which the patient is currently in complete remission, and
  • Any other cancer from which the patient has been disease-free for at least 1 year
• Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk, interfere with the patient's participation in the study, or hinder evaluation of study results

• Pregnant or nursing. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study therapy.

  • Note: Pregnant women are excluded from this study because MLN4924 (pevonedistat) is a NEDD8 inhibitor with the potential for teratogenic or abortifacient effects and because belinostat may cause teratogenicity and/or embryo-fetal lethality by virtue of targeting actively dividing cells. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with MLN4924 (pevonedistat) or belinostat, breastfeeding should be discontinued if the mother is treated with MLN4924 (pevonedistat)/belinostat

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (belinostat, pevonedistat); Patients receive belinostat IV daily over 30 minutes on days 1-5 and pevonedistat IV QD over 60 minutes on days 1, 3, and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: Pevonedistat; Given IV; Other Names: MLN4924; Nedd8-Activating Enzyme Inhibitor MLN4924; Drug: Belinostat; Given IV; Other Names: PXD101; Beleodaq; PXD 101; PXD-101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase 2 Dose (RP2D) for the Combination of MLN4924 (Pevonedistat) and Belinostat	Determined by the number of patients with treatment dosing level toxicities (DLT's). DLT's will be defined in cycle 1 as pre-specified adverse events that are considered by the investigator to be related to therapy with MLN4924 (pevonedistat) and/or belinostat.	Up to the end of cycle 1, 21 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events (AEs)	Number of graded Adverse Events (AEs) reported using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.	Adverse Events (AE's) were collected starting Cycle 1 Day 1 through 30 days following treatment up to 1 year, 6 months.
Treatment Response	The percentage of participants that experience a decrease in tumor size (partial response), or disappearance of tumor (complete response), classified according to International Working Group (IWG) and European Leukemia Net (ELN) criteria for response assessment in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).	From day 1 until final response measured, up to 188 days.
Duration of Stable and Complete Response	Number of days patients remained in stable or complete response.	From documentation of tumor response to disease progression or death assessed up to 188 days.
Time to Response	Number of days from day 1 of therapy to best response.	From Day 1 of protocol treatment to the time of documentation of tumor response, assessed up to 188 days.
Change in MLN4924 Belinostat Plasma Concentrations	Pharmacokinetic parameters in MLN4924 belinostat will be calculated using standard non-compartmental methods and summarized as geometric mean and geometric coefficient of variation.	Baseline up to cycle 1 day 1
Change in MLN4924 Pevonedistat Plasma Concentrations	Pharmacokinetic (PK) parameters in MLN4924 pevonedistat will be calculated using standard non-compartmental methods and summarized as geometric mean and geometric coefficient of variation.	Baseline up to cycle 1 day 1
Change in MLN4924 Belinostat Glucuronide Plasma Concentrations	Pharmacokinetic parameters in MLN4924 belinostat glucuronide will be calculated using standard non-compartmental methods and summarized as geometric mean and geometric coefficient of variation.	Baseline up to cycle 1 day 1

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine What Relationship, if Any, Exists Between Such Responses and TP53/FLT3 Mutational Status.	TP53 and FLT3 mutational status by NGS compared to best clinical response classified according to International Working Group (IWG) and European Leukemia Net (ELN) criteria for response assessment in AML and MDS using a specific hematologic and blast count thresholds to define outcomes like Complete Remission (CR) or Hematologic Improvement (HI), focusing on blood counts (Hb, ANC, Platelets) and bone marrow (BM) blasts, with recent updates (IWG 2023/2024) emphasizing clearer definitions, limited recovery categories (CRi, CRL), and incorporating transfusion dependency/independence for better clinical relevance. Scoring isn't a single number but categorizing responses (CR, CRi, HI, Failure).	Screening
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples gH2A.X	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples Phosphorylated Checkpoint Kinase 1 (p-Chk1)	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples Phosphorylated FANCD2 (p-FANCD2)	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples Myeloid Cell Leukemia Sequence 1 (MCL-1)	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples Protein BCL-xL	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples Anti-apoptotic Protein BCL-2	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples p-Wee1 Kinase	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples Histone H4 Acetylation at Lysine 16	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples Bcl-2 Interacting Mediator of Cell Death (BIM)	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples Chromatin Licensing and DNA Replication Factor 1 (Cdt-1)	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs
Change in Candidate Biomarker Levels in Bone Marrow and/or Blood Samples C-terminal Binding Protein Interacting Protein (CtlP)	Paired t-tests will be used to determine if there is a significant change in each of the candidate biomarker between the pre- and 24-hour post-treatment assessments, in bone marrow samples and/or blood samples.	Baseline up to 24 hours post-treatment with the first doses of study drugs

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Keri R Maher, University Health Network Princess Margaret Cancer Center LAO

Publications and helpful links

General Publications

• Maher KR, Shafer D, Schaar D, Bandyopadhyay D, Deng X, Wright J, Piekarz R, Rudek MA, Harvey RD, Grant S. A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Cancer Chemother Pharmacol. 2025 Jan 17;95(1):24. doi: 10.1007/s00280-024-04742-9.

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2019
• Primary Completion (Actual): September 6, 2022
• Study Completion (Actual): May 8, 2025

Study Registration Dates

• First Submitted: December 11, 2018
• First Submitted That Met QC Criteria: December 11, 2018
• First Posted (Actual): December 12, 2018

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 11, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Histone Deacetylase Inhibitors; belinostat; pevonedistat
• Other Study ID Numbers: NCI-2018-03227 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186644 (U.S. NIH Grant/Contract); 10246 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No