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Acute Myeloid Leukemia Arising From Previous Myelodysplastic SyndromePhase 1NCT03813147

Pevonedistat, Azacitidine, Fludarabine Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

A Phase 1 study testing Azacitidine, Cytarabine and Fludarabine Phosphate in people with Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome and Recurrent Acute Myeloid Leukemia, run by National Cancer Institute (NCI) at 19 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This phase I trial studies the side effects and how well pevonedistat, azacitidine, fludarabine phosphate, and cytarabine work in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (relapsed) or has not responded to treatment (refractory). Read more about this study

Who is it for?
Ages 1 month to 21 years
What is being tested?
Azacitidine, Cytarabine and Fludarabine Phosphate
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
19 sitesUnited States
Study dates
17 May 2019to 31 Dec 2023
Phase
Phase 1

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 1 month to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Patients must have had histologic verification of AML at the original diagnosis. Patients must have one of the following:
  • Recurrent disease in >= 1st relapse with >= 5% blasts in the bone marrow (M2/M3) marrow OR immunophenotypic evidence of disease with >= 0.1% blasts detected by flow cytometry, OR evidence of recurrent cytogenetic or molecular abnormalities consistent with relapse, with or without extramedullary disease
  • Refractory AML is defined as >= 5% blasts in the bone marrow (M2/M3) after >= 2 induction attempts (i.e., 2 cycles of chemotherapy)
  • Patients with advanced MDS, including MDS that has progressed to AML, and have experienced relapse or are refractory after >= 1 course of induction therapy, are eligible
  • Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age
  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately
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  • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive
  • >= 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. Additionally, patients must have recovered from all acute toxic effects of prior therapy
  • NOTE: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy
  • Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil [ANC] counts): >= 7 days after the last dose of agent
  • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
  • Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator
  • Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
  • Stem cell Infusions (with or without traumatic brain injury [TBI]):
  • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor leukocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
  • Autologous stem cell infusion including boost infusion: >= 42 days
  • Cellular Therapy: >= 30 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
  • Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 42 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial brain metastases (BM) radiation
  • Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131 iodine [I]-metaiodobenzylguanidine [MIBG]): >= 42 days after systemically administered radiopharmaceutical therapy
  • Patients must not have received prior exposure to MLN4924 (pevonedistat)
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
  • 1 month to < 6 months; 0.4 (male and female)
  • 6 months to < 1 year; 0.5 (male and female)
  • 1 to < 2 years; 0.6 (male and female)
  • 2 to < 6 years; 0.8 (male and female)
  • 6 to < 10 years; 1 (male and female)
  • 10 to < 13 years; 1.2 (male and female)
  • 13 to < 16 years; 1.5 (male) and 1.4 (female)
  • >= 16 years; 1.7 (male) and 1.4 (female)
  • Bilirubin (sum of conjugated + unconjugated) =< upper limit of normal (ULN) for age
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN. For the purpose of this study, the ULN for serum glutamate pyruvate transaminase (SGPT) is 45 U/L
  • Shortening fraction of >= 27% by echocardiogram, or
  • Ejection fraction of >= 50% by echocardiogram or radionuclide angiogram
  • No ventricular or supraventricular arrhythmia on electrocardiogram (EKG)
  • Prolonged rate corrected QT (QTc) interval < 500 msec
  • Pulse oximetry > 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest)
  • International normalized ratio (INR) =< 1.5
  • Hemoglobin > 8.0 g/dL (may receive red blood cell [RBC] transfusions)
  • All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines

Who cannot join

  • Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use 1 highly effective and 1 additional effective (barrier) method of contraception at the same time for the duration of study therapy and for 4 months after the completion of MLN4924 (pevonedistat) administration. True abstinence, when this is in line with the preferred and usual lifestyle of the subject, is acceptable. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception
  • Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
  • Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are not eligible (except hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy)
  • Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other systemic agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial. Topical immunosuppressive agents (e.g. topical steroids) are allowed. Physiologic replacement of hydrocortisone is allowed
  • Patients who are taking drugs that are strong CYP3A4 inducers and cannot be switched to alternative drugs 14 days prior to enrollment are not eligible. Strong inducers of CYP34 are not permitted during the study
  • Patients with known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection are not eligible. NOTE: Patients who have isolated positive hepatitis B core antibody (i.e. in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load
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  • Patients with known hepatic cirrhosis or severe pre-existing hepatic impairment are not eligible
  • Patients with uncontrolled high blood pressure (i.e., >= 99% for age) are not eligible
  • Patients with any of the following diagnoses:
  • Acute promyelocytic leukemia
  • Down syndrome
  • Juvenile myelomonocytic leukemia
  • Patients who have a documented active uncontrolled infection are not eligible
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition as the study agent
  • Patients with human immunodeficiency virus (HIV) are not eligible unless they meet all of the following criteria:
  • CD4 count > 350 cell/mm^3
  • Undetectable viral load
  • Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents
  • No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections
  • 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) are not eligible
  • 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) are not eligible

Trial locations and contacts

19 sites in 1 country.

19 sites in 1 country

United States19 sites

  • C S Mott Children's Hospital

    Ann Arbor, Michigan, 48109

  • Children's Healthcare of Atlanta - Egleston

    Atlanta, Georgia, 30322

  • Children's Hospital Colorado

    Aurora, Colorado, 80045

  • Children's Hospital of Alabama

    Birmingham, Alabama, 35233

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Lurie Children's Hospital-Chicago

    Chicago, Illinois, 60611

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

  • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

    Houston, Texas, 77030

  • Riley Hospital for Children

    Indianapolis, Indiana, 46202

  • Saint Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • University of Minnesota/Masonic Cancer Center

    Minneapolis, Minnesota, 55455

  • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

    New York, New York, 10032

  • Children's Hospital of Orange County

    Orange, California, 92868

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Children's Hospital of Pittsburgh of UPMC

    Pittsburgh, Pennsylvania, 15224

  • UCSF Medical Center-Mission Bay

    San Francisco, California, 94158

  • Seattle Children's Hospital

    Seattle, Washington, 98105

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

Official title: A Feasibility Trial of MLN4924 (Pevonedistat, TAK 924) Given in Combination With Azacitidine, Fludarabine, and Cytarabine, in Children, Adolescents, and Young Adults With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

This phase I trial studies the side effects and how well pevonedistat, azacitidine, fludarabine phosphate, and cytarabine work in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (relapsed) or has not responded to treatment (refractory). Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, fludarabine phosphate, and cytarabine, 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. Giving more than one drug (combination chemotherapy) and pevonedistat may work better in treating patients with acute myeloid leukemia or myelodysplastic syndrome.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To evaluate the tolerability and feasibility of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine phosphate (fludarabine), and cytarabine re-induction for pediatric patients with recurrent/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

II. To define and describe the toxicities of MLN4924 (pevonedistat) when given in combination with azacitidine, fludarabine, and cytarabine to pediatric patients with relapsed/refractory AML and MDS.

III. To characterize the pharmacokinetics of MLN4924 (pevonedistat) in children with recurrent or refractory AML and MDS.

SECONDARY OBJECTIVE:

  1. To describe the antitumor activity of MLN4924 (pevonedistat) in combination with azacitidine, fludarabine, and cytarabine within the confines of a feasibility study.

EXPLORATORY OBJECTIVES:

  1. To describe the effect of MLN4924 (pevonedistat) administered on this schedule on messenger ribonucleic acid (mRNA) transcript levels of genes known to be induced by MLN4924 (pevonedistat) mediated NEDD8 activating enzyme (NAE) inhibition.

II. To describe the effect of MLN4924 (pevonedistat) on NEDDylation of proteins in the NEDD8 pathway that are likely to be affected by NAE inhibition with MLN4924 (pevonedistat).

OUTLINE:

Patients receive cytarabine intrathecally on day 0 at least 24 hours prior to the start of each cycle. Patients then receive azacitidine intravenously (IV) over 15 minutes once daily (QD) on days 1-5, pevonedistat IV over 60 minutes on days 1, 3, and 5, and fludarabine phosphate IV over 30 minutes QD and cytarabine IV over 1-3 hours QD on days 6-10. Patients with central nervous system (CNS)2 or CNS3 receive cytarabine intrathecally or methotrexate intrathecally, hydrocortisone intrathecally, and cytarabine intrathecally on days 8 and 11-34. Cycles continue for 35 days in the absence of disease progression or unacceptable toxicity. Patients with stable or greater with non-hematologic toxicities probably or definitely related to pevonedistat may receive an additional cycle of treatment.

After completion of study treatment, patients are followed up for 30 days.

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.

  • AzacitidineDrug

    Also called 5 AZC, 5-AC, 5-Azacitidine, 5-Azacytidine

    Given IV

  • CytarabineDrug

    Also called .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone

    Given intrathecally and IV

  • Fludarabine PhosphateDrug

    Also called 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara

    Given IV

  • MethotrexateDrug

    Also called Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate

    Given intrathecally

  • PevonedistatDrug

    Also called MLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924

    Given IV

  • Therapeutic HydrocortisoneDrug

    Also called Aeroseb-HC, Barseb HC, Barseb-HC, Cetacort

    Given intrathecally

Study groups in NCT03813147
Study groupRoleWhat they receive
Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)ExperimentalPatients receive cytarabine intrathecally on day 0 at least 24 hours prior to the start of each cycle. Patients then receive azacitidine IV over 15 minutes QD on days 1-5, pevonedistat IV over 60 minutes on days 1, 3, and 5, and fludarabine phosphate IV over 30 minutes QD and cytarabine IV over 1-3 hours QD on days 6-10. Patients with CNS2 or CNS3 receive cytarabine intrathecally or methotrexate intrathecally, hydrocortisone intrathecally, and cytarabine intrathecally on days 8 and 11-34. Cycles continue for 35 days in the absence of disease progression or unacceptable toxicity. Patients with stable or greater with non-hematologic toxicities probably or definitely related to pevonedistat may receive an additional cycle of treatment.
Receives: Drug: Azacitidine; Drug: Cytarabine; Drug: Fludarabine Phosphate; Drug: Methotrexate; Drug: Pevonedistat; Drug: Therapeutic Hydrocortisone

What is being measured

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

  1. Number of Participants With Dose Limiting Toxicities of MLN4924 (Pevonedistat)

    Frequency of patients with dose limiting toxicity in the first cycle of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level among patients in the dose escalation cohort.

    Measured: Up to 35 days

  2. Number of Participants With Adverse Events Attributable to MLN4924 (Pevonedistat)

    Frequency of patients with at least one grade 3 adverse event at least possibly attributable to MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level.

    Measured: Up to 70 days

  3. Area Under the Plasma Concentration Versus Time Curve of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS

    Median (Range) of the area under the plasma concentration versus time curve of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.

    Measured: Up to 5 days

  4. Total Plasma Clearance of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS

    Median (Range) of the total plasma clearance of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.

    Measured: Up to 5 days

  5. Elimination Half-life of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS

    Median (Range) of the elimination half-life of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.

    Measured: Up to 5 days

  6. Maximum Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS

    Median (Range) of the maximum concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.

    Measured: Up to 5 days

  7. Maximum Time to Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS

    Median (Range) of the maximum time to concentration of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS by dose level measured pre-dose, end of infusion, 4-6 hours, and 24 hours post-dose infusion on Days 1 and 5.

    Measured: Up to 5 days

Secondary outcomes (1)

  1. Number of Participants With Antitumor Activity of MLN4924 (Pevonedistat)

    Frequency of participants with best overall response by dose level of PR or CR for MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction Per Response Evaluation Criteria for CR (M1 bone marrow (< 5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral blood counts (ANC > 1000/uL and platelet count > 100,000/uL), CRp (M1 bone marrow (< 5% blasts) and no evidence of circulating blasts or extramedullary disease and with recovery of ANC > 1000/uL and platelet transfusion independence), CRi (M1 bone marrow (<5% blasts) and no evidence of circulating blasts or extramedullary disease and with ANC < 1000/uL or platelet count < 100,000/uL without platelet transfusion independence), or PR (M2 marrow status (> 5% or < 25% blasts cells) and at least 50% decrease in bone marrow blast percent from baseline.

    Measured: Up to 1 year

Timeline

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

  1. First posted23 Jan 2019
  2. Study start17 May 2019
  3. Primary completion30 Sep 2021
  4. Study completion31 Dec 2023

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
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03813147
Sponsor's protocol ID
NCI-2019-00215
Other IDs
NCI-2019-00215, ADVL1712, ADVL1712
Status last verified
Mar 2025
First submitted
21 Jan 2019
Last updated
13 Apr 2025
Data monitoring committee
Yes
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

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