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

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ClinicalTrials.gov Identifier: NCT03813147
Recruitment Status : Active, not recruiting
First Posted : January 23, 2019
Last Update Posted : March 12, 2021
Sponsor:
Collaborator:
Children's Oncology Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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). 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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Recurrent Myelodysplastic Syndrome Refractory Acute Myeloid Leukemia Refractory Myelodysplastic Syndrome Drug: Azacitidine Drug: Cytarabine Drug: Fludarabine Phosphate Drug: Methotrexate Drug: Pevonedistat Drug: Therapeutic Hydrocortisone Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. 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:

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

EXPLORATORY OBJECTIVES:

I. 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 1, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
Experimental: Treatment (cytarabine, azacitidine, pevonedistat, fludarabine)
Patients 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.
Drug: Azacitidine
Given IV
Other Names:
  • 5 AZC
  • 5-AC
  • 5-Azacytidine
  • 5-AZC
  • Azacytidine
  • Azacytidine, 5-
  • Ladakamycin
  • Mylosar
  • Onureg
  • U-18496
  • Vidaza

Drug: Cytarabine
Given intrathecally and IV
Other Names:
  • .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
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-Cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Drug: Methotrexate
Given intrathecally
Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • CL 14377
  • CL-14377
  • Emtexate
  • Emthexat
  • Emthexate
  • Farmitrexat
  • Fauldexato
  • Folex
  • Folex PFS
  • Lantarel
  • Ledertrexate
  • Lumexon
  • Maxtrex
  • Medsatrexate
  • Metex
  • Methoblastin
  • Methotrexate LPF
  • Methotrexate Methylaminopterin
  • Methotrexatum
  • Metotrexato
  • Metrotex
  • Mexate
  • Mexate-AQ
  • MTX
  • Novatrex
  • Rheumatrex
  • Texate
  • Tremetex
  • Trexeron
  • Trixilem
  • WR-19039

Drug: Pevonedistat
Given IV
Other Names:
  • MLN4924
  • Nedd8-Activating Enzyme Inhibitor MLN4924

Drug: Therapeutic Hydrocortisone
Given intrathecally
Other Names:
  • Aeroseb-HC
  • Barseb HC
  • Barseb-HC
  • Cetacort
  • Cort-Dome
  • Cortef
  • Cortenema
  • Cortifan
  • Cortisol
  • Cortispray
  • Cortril
  • Dermacort
  • Domolene
  • Eldecort
  • Hautosone
  • Heb-Cort
  • Hydrocortisone
  • Hydrocortone
  • Hytone
  • Komed-HC
  • Nutracort
  • Proctocort
  • Rectoid




Primary Outcome Measures :
  1. Dose limiting toxicities of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS [ Time Frame: Up to 35 days ]
    Frequency and percent 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.

  2. Frequency of adverse events [ Time Frame: Up to 70 days ]
    Frequency and percent of patients with adverse events 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 stratified by type of adverse event and dose level.

  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 [ Time Frame: Up to 5 days ]
    Median (min, max) 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.

  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 [ Time Frame: Up to 5 days ]
    Median (min, max) 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.

  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 [ Time Frame: Up to 5 days ]
    Median (min, max) 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.

  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 [ Time Frame: Up to 5 days ]
    Median (min, max) 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.

  7. Minimum 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 [ Time Frame: Up to 5 days ]
    Median (min, max) of the minimum 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.


Secondary Outcome Measures :
  1. Antitumor activity 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 [ Time Frame: Up to 1 year ]
    Frequency with percent of participants with at least partial response 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.


Other Outcome Measures:
  1. Messenger ribonucleic acid (mRNA) transcript levels 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 [ Time Frame: Up to 5 days ]
    Median (min, max) transcript levels 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Month to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

    • 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

Exclusion Criteria:

  • 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03813147


Locations
Show Show 19 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Children's Oncology Group
Investigators
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Principal Investigator: Katherine G Tarlock COG Phase I Consortium
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03813147    
Other Study ID Numbers: NCI-2019-00215
NCI-2019-00215 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ADVL1712 ( Other Identifier: Pediatric Early Phase Clinical Trial Network )
ADVL1712 ( Other Identifier: CTEP )
First Posted: January 23, 2019    Key Record Dates
Last Update Posted: March 12, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
Methotrexate
Fludarabine phosphate
Azacitidine
Fludarabine
Enzyme Inhibitors
Pevonedistat
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites