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Recurrent Acute Myeloid LeukemiaPhase 1NCT03772925

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

A Phase 1 study testing Belinostat and Pevonedistat in people with Recurrent Acute Myeloid Leukemia and Recurrent Myelodysplastic Syndrome, run by National Cancer Institute (NCI) at 6 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Belinostat and Pevonedistat
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
18 participants
Where
6 sitesUnited States
Study dates
20 Jun 2019to 8 May 2025
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
Show all 19Show fewer
  • 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

Who cannot join

  • 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)
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  • 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

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • UT Southwestern/Simmons Cancer Center-Dallas

    Dallas, Texas, 75390

  • Rutgers Cancer Institute of New Jersey

    New Brunswick, New Jersey, 08903

  • Virginia Commonwealth University/Massey Cancer Center

    Richmond, Virginia, 23298

  • Moffitt Cancer Center-International Plaza

    Tampa, Florida, 33607

  • Moffitt Cancer Center - McKinley Campus

    Tampa, Florida, 33612

  • Moffitt Cancer Center

    Tampa, Florida, 33612

Other trials in United States

About this study

Official title: 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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. 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:

  1. 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.

  1. 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.

Being tested
Belinostat, Pevonedistat
Medical subject headings
Leukemia, Myeloid, Acute, Myelodysplastic Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BelinostatDrug

    Also called Beleodaq, PXD 101, PXD-101, PXD101

    Given IV

  • PevonedistatDrug

    Also called MLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924

    Given IV

Study groups in NCT03772925
Study groupRoleWhat they receive
Treatment (belinostat, pevonedistat)ExperimentalPatients 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.
Receives: Drug: Belinostat; Drug: Pevonedistat

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to the end of cycle 1, 21 days.

Secondary outcomes (7)

  1. 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.

    Measured: Adverse Events (AE's) were collected starting Cycle 1 Day 1 through 30 days following treatment up to 1 year, 6 months.

  2. 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).

    Measured: From day 1 until final response measured, up to 188 days.

  3. Duration of Stable and Complete Response

    Number of days patients remained in stable or complete response.

    Measured: From documentation of tumor response to disease progression or death assessed up to 188 days.

  4. Time to Response

    Number of days from day 1 of therapy to best response.

    Measured: From Day 1 of protocol treatment to the time of documentation of tumor response, assessed up to 188 days.

  5. 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.

    Measured: Baseline up to cycle 1 day 1

  6. 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.

    Measured: Baseline up to cycle 1 day 1

  7. 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.

    Measured: Baseline up to cycle 1 day 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Dec 2018
  2. Study start20 Jun 2019
  3. Primary completion6 Sep 2022
  4. Study completion8 May 2025

Why it stopped: Drug supply issues

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
18 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03772925
Sponsor's protocol ID
NCI-2018-03227
Other IDs
NCI-2018-03227, 10246, 10246, UM1CA186644
Status last verified
Feb 2026
First submitted
11 Dec 2018
Last updated
3 Mar 2026
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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

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.

    PubMed 39821392

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Belinostat and Pevonedistat in people with Recurrent Acute Myeloid Leukemia and Recurrent Myelodysplastic Syndrome, run by National Cancer Institute (NCI) at 6 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 53 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 3 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Mar 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Recommended Phase 2 Dose (RP2D) for the Combination of MLN4924 (Pevonedistat) and Belinostat (time frame: Up to the end of cycle 1, 21 days.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03772925, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Mar 2026.

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