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TerminatedNCT03772925Updated Mar 3, 2026Results posted

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

A Phase 1 interventional study of Belinostat and Pevonedistat in Recurrent Acute Myeloid Leukemia, Recurrent Myelodysplastic Syndrome and Refractory Acute Myeloid Leukemia, sponsored by National Cancer Institute (NCI). Terminated at 6 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-03-03.

Sponsored by National Cancer Institute (NCI) · Phase 1, Interventional, and Treatment

Why this study was terminated
Drug supply issues
Phase
Phase 1
Study type
Interventional
Enrollment
18
Allocation
Not applicable
Ages
18 Years and older
Sex
All
01

Study 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). 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:

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.

02

Conditions studied

  • Recurrent Acute Myeloid Leukemia
  • Recurrent Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory Myelodysplastic Syndrome
03

In context

Leukemia, Myeloid, Acute

2,971 studies on the registry are indexed under Leukemia, Myeloid, Acute; 745 are open to participants now.

This study's enrollment of 18 is below the median of 41 across 2,509 interventional studies indexed under Leukemia, Myeloid, Acute.

Browse Leukemia, Myeloid, Acute studies →

Lead sponsor

National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.

Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
18 participants (actual)

Study arms

  • 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: Belinostat · Drug: Pevonedistat

Interventions

  • DrugBelinostat

    Given IV

    Also known as: Beleodaq, PXD 101, PXD-101, PXD101

  • DrugPevonedistat

    Given IV

    Also known as: MLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924

06

What researchers measure

Primary outcomes

  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.

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

Secondary outcomes

  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.

    Time frame: 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).

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: Baseline up to cycle 1 day 1

Other outcomes

  1. 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).

    Time frame: Screening

  2. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

  3. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

  4. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

  5. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

  6. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

  7. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

  8. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

  9. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

  10. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

  11. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

  12. 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.

    Time frame: Baseline up to 24 hours post-treatment with the first doses of study drugs

07

Results

Posted Mar 3, 2026
Limitations and caveats
Takeda stopped producing Pevonedistat

Participant flow

Participant flow — Overall Study
MilestoneTreatment (Belinostat, Pevonedistat) Dose Level 1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
Started33345
Completed33343
Not completed00002
Withdrew: Adverse event00001
Withdrew: Physician decision00001

Outcome measures

PrimaryRecommended 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.

Time frame:
Up to the end of cycle 1, 21 days.
Reported as:
Count of participants · Participants
Recommended Phase 2 Dose (RP2D) for the Combination of MLN4924 (Pevonedistat) and Belinostat
ParticipantsTreatment (Belinostat, Pevonedistat) Dose Level 1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
Recommended Phase 2 Dose (RP2D) for the Combination of MLN4924 (Pevonedistat) and Belinostat00000
SecondaryIncidence 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.

Time frame:
Adverse Events (AE's) were collected starting Cycle 1 Day 1 through 30 days following treatment up to 1 year, 6 months.
Reported as:
Number · Adverse Events Reported
Incidence of Adverse Events (AEs)
Adverse Events ReportedTreatment (Belinostat, Pevonedistat) Dose Level 1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
Number of Grade 1 AE's57347549127
Number of Grade 2 AE's1911694217
Number of Grade 3 AE's13633197
Number of Grade 4 AE's14951
Number of Grade 5 AE's10100
SecondaryTreatment 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).

Time frame:
From day 1 until final response measured, up to 188 days.
Reported as:
Count of participants · Participants
Treatment Response
ParticipantsTreatment (Belinostat, Pevonedistat) Dose Level1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
Complete Response00010
Stable Disease00202
Progression23103
Partial Response00000
SecondaryDuration of Stable and Complete Response

Number of days patients remained in stable or complete response.

Time frame:
From documentation of tumor response to disease progression or death assessed up to 188 days.
Reported as:
Mean · Days
Duration of Stable and Complete Response
DaysTreatment (Belinostat, Pevonedistat) Dose Level 1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
Duration of Stable and Complete Response——95.0 (42 to 148)4.0 (4 to 4)125.5 (63 to 188)
SecondaryTime to Response

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

Time frame:
From Day 1 of protocol treatment to the time of documentation of tumor response, assessed up to 188 days.
Reported as:
Mean · Days
Time to Response
DaysTreatment (Belinostat, Pevonedistat) Dose Level 1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
Time to Response31.5 (28 to 35)35.3 (35 to 36)35.3 (34 to 36)122.0 (122 to 122)40.6 (11 to 98)
SecondaryChange 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.

Time frame:
Baseline up to cycle 1 day 1
Reported as:
Mean · ng/ml
Change in MLN4924 Belinostat Plasma Concentrations
ng/mlTreatment (Belinostat, Pevonedistat) Dose Level 1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
Change in MLN4924 Belinostat Plasma Concentrations109.0 ± 144.5119.6 ± 50.3124.9 ± 35.096.5 ± 46.0113.7 ± 29.4
SecondaryChange 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.

Time frame:
Baseline up to cycle 1 day 1
Reported as:
Mean · ng/ml
Change in MLN4924 Pevonedistat Plasma Concentrations
ng/mlTreatment (Belinostat, Pevonedistat) Dose Level 1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
Change in MLN4924 Pevonedistat Plasma Concentrations278 ± 311372 ± 93.2897 ± 26.0841 ± 455—
SecondaryChange 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.

Time frame:
Baseline up to cycle 1 day 1
Reported as:
Mean · ng/ml
Change in MLN4924 Belinostat Glucuronide Plasma Concentrations
ng/mlTreatment (Belinostat, Pevonedistat) Dose Level 1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
Change in MLN4924 Belinostat Glucuronide Plasma Concentrations178.4 ± 246.7141.9 ± 18.8144.2 ± 30.0214.0 ± 86.8193.0 ± 18.8
Other pre-specifiedDetermine 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).

Time frame:
Screening

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Other pre-specifiedChange 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.

Time frame:
Baseline up to 24 hours post-treatment with the first doses of study drugs

Results for this outcome have not been posted.

Adverse events

Collected over Adverse Events (AE's) were collected starting Cycle 1 Day 1 through 30 days following treatment up to 1 year, 6 months.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Treatment (Belinostat, Pevonedistat) Dose Level 11/3 (33.3%)1/3 (33.3%)3/3 (100%)
Treatment (Belinostat, Pevonedistat) Dose Level 20/3 (0%)1/3 (33.3%)3/3 (100%)
Treatment (Belinostat, Pevonedistat) Dose Level 31/3 (33.3%)2/3 (66.7%)3/3 (100%)
Treatment (Belinostat, Pevonedistat) Dose Level 40/4 (0%)2/4 (50%)4/4 (100%)
Treatment (Belinostat, Pevonedistat) Dose Level 50/5 (0%)2/5 (40%)5/5 (100%)
Most frequent serious events
Showing 10 of 11
Most frequent serious events
EventTreatment (Belinostat, Pevonedistat) Dose Level 1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
Atrial FlutterCardiac disorders0/31/30/30/40/5
Catheter Related InfectionInfections and infestations1/30/30/30/40/5
ChillsGeneral disorders1/30/30/30/40/5
Disease Progression w DeathGeneral disorders0/30/31/30/40/5
FungemiaInfections and infestations0/30/31/30/40/5
FatigueGeneral disorders0/30/31/30/40/5
HypertensionVascular disorders0/30/30/31/41/5
Pain in ExtremityMusculoskeletal and connective tissue disorders0/30/30/31/41/5
Peripheral motor NeuropathyNervous system disorders0/30/30/31/40/5
Chest PainCardiac disorders0/30/30/30/41/5
Most frequent other events
Showing 10 of 113
Most frequent other events
EventTreatment (Belinostat, Pevonedistat) Dose Level 1Treatment (Belinostat, Pevonedistat) Dose Level 2Treatment (Belinostat, Pevonedistat) Dose Level 3Treatment (Belinostat, Pevonedistat) Dose Level 4Treatment (Belinostat, Pevonedistat) Dose Level 5
AnemiaBlood and lymphatic system disorders1/33/33/32/40/5
Platelet count decreasedInvestigations1/33/33/33/40/5
White blood cell decreasedInvestigations1/30/33/32/40/5
DyspneaRespiratory, thoracic and mediastinal disorders1/30/33/30/42/5
NauseaGastrointestinal disorders1/32/32/32/44/5
Electrocardiogram QT corrected intervInvestigations1/30/31/31/44/5
ConstipationGastrointestinal disorders1/30/32/31/41/5
Fecal incontinenceGastrointestinal disorders2/30/30/30/40/5
ChillsGeneral disorders2/30/30/30/41/5
FatigueGeneral disorders1/32/32/32/41/5

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Treatment (Belinostat, Pevonedistat) Dose 1Treatment (Belinostat, Pevonedistat) Dose 2Treatment (Belinostat, Pevonedistat) Dose 3Treatment (Belinostat, Pevonedistat) Dose 4Treatment (Belinostat, Pevonedistat) Dose 5Total
<=18 years000000
Between 18 and 65 years220318
>=65 years1131410
Sex: Female, Male
Sex: Female, Male(Participants)Treatment (Belinostat, Pevonedistat) Dose 1Treatment (Belinostat, Pevonedistat) Dose 2Treatment (Belinostat, Pevonedistat) Dose 3Treatment (Belinostat, Pevonedistat) Dose 4Treatment (Belinostat, Pevonedistat) Dose 5Total
Female2214312
Male112026
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Treatment (Belinostat, Pevonedistat) Dose 1Treatment (Belinostat, Pevonedistat) Dose 2Treatment (Belinostat, Pevonedistat) Dose 3Treatment (Belinostat, Pevonedistat) Dose 4Treatment (Belinostat, Pevonedistat) Dose 5Total
Hispanic or Latino010102
Not Hispanic or Latino3233415
Unknown or Not Reported000011
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Treatment (Belinostat, Pevonedistat) Dose 1Treatment (Belinostat, Pevonedistat) Dose 2Treatment (Belinostat, Pevonedistat) Dose 3Treatment (Belinostat, Pevonedistat) Dose 4Treatment (Belinostat, Pevonedistat) Dose 5Total
American Indian or Alaska Native000000
Asian000000
Native Hawaiian or Other Pacific Islander000000
Black or African American102126
White2212310
More than one race000000
Unknown or Not Reported010102
Region of Enrollment
Region of Enrollment(participants)Treatment (Belinostat, Pevonedistat) Dose 1Treatment (Belinostat, Pevonedistat) Dose 2Treatment (Belinostat, Pevonedistat) Dose 3Treatment (Belinostat, Pevonedistat) Dose 4Treatment (Belinostat, Pevonedistat) Dose 5Total
United States3334518
Disease Histology
Disease Histology(Participants)Treatment (Belinostat, Pevonedistat) Dose 1Treatment (Belinostat, Pevonedistat) Dose 2Treatment (Belinostat, Pevonedistat) Dose 3Treatment (Belinostat, Pevonedistat) Dose 4Treatment (Belinostat, Pevonedistat) Dose 5Total
Acute Myeloid Leukemia (AML)3224516
Myelodysplastic Syndrome (MDS)011002
08

Study locations

6 sites
  • Moffitt Cancer Center-International Plaza
    Tampa, Florida 33607, United States
  • Moffitt Cancer Center - McKinley Campus
    Tampa, Florida 33612, United States
  • Moffitt Cancer Center
    Tampa, Florida 33612, United States
  • Rutgers Cancer Institute of New Jersey
    New Brunswick, New Jersey 08903, United States
  • UT Southwestern/Simmons Cancer Center-Dallas
    Dallas, Texas 75390, United States
  • Virginia Commonwealth University/Massey Cancer Center
    Richmond, Virginia 23298, United States
09

References and documents

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 ↗

Study documents

  • Protocol and statistical analysis plan · Feb 16, 2022
  • Informed consent form · Feb 16, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: 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

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Mar 3, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT03772925
Lead sponsor
National Cancer Institute (NCI)
Responsible party
Sponsor
First posted
Dec 12, 2018
Start date
Jun 20, 2019
Primary completion
Sep 6, 2022
Completion
May 8, 2025
Results posted
Mar 3, 2026
Last update
Mar 3, 2026

Study contacts

Keri R Maher
principal investigator · University Health Network Princess Margaret Cancer Center LAO

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is terminated, as verified in Feb 2026. You cannot join it, but the record below documents what was studied.

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