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

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ClinicalTrials.gov Identifier: NCT03813147
Recruitment Status : Recruiting
First Posted : January 23, 2019
Last Update Posted : October 18, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE January 21, 2019
First Posted Date  ICMJE January 23, 2019
Last Update Posted Date October 18, 2019
Actual Study Start Date  ICMJE May 1, 2019
Estimated Primary Completion Date August 21, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 21, 2019)
  • Incidence of adverse events [ Time Frame: Up to 35 days (1 cycle) ]
    Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
  • Dose-limiting toxicities (DLTs) [ Time Frame: Up to 35 days (1 cycle of treatment) ]
    The maximum-tolerated dose (MTD) will be the maximum dose at which fewer than one-third of patients experience DLT. A descriptive summary of all toxicities will be reported.
  • Pharmacokinetics (PK) of MLN4924 (pevonedistat) [ Time Frame: Days 1 and 5 of cycle 1 ]
    PK of pevonedistat will be performed in serum at different time points depending on the weight of the patient. For patients =< 10 kg, PK will be performed prior to infusion, at the end of infusion, and 4-6 and 24 hours after infusion on days 1 and 5 of cycle 1. For patients > 10 kg, PK will be performed prior to infusion, at the end of infusion, 1, 2, 4, 6-8, and 24 hours after infusion on days 1 and 5 of cycle 1. It will also be performed 48 hours after infusion on day 1 and 48 or 72 hours after infusion on day 5 of cycle 1. A descriptive analysis of PK parameters of pevonedistat will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03813147 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 21, 2019)
Antitumor activity [ Time Frame: Up to 1 year ]
Disease response will be assessed according to criteria for patients with acute myeloid leukemia (AML), and will be reported descriptively.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: January 21, 2019)
Effect of pevonedistat on messenger ribonucleic acid (mRNA) transcript levels [ Time Frame: Up to 6 hours post pevonedistat dose on day 5 during cycle 1 ]
Peripheral blood will be collected from consenting patients to evaluate the effects of pevonedistat on mRNA transcript levels of genes that have been shown to be induced by pevonedistat mediated Nedd8 activating enzyme (NAE) inhibition.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Pevonedistat, Azacitidine, Fludarabine Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed High-Risk Myelodysplastic Syndrome
Official Title  ICMJE A Feasibility Trial of MLN4924 (Pevonedistat,TAK924) Given in Combination With Azacitidine, Fludarabine, and Cytarabine, in Children, Adolescents, and Young Adults With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed Myelodysplastic Syndrome
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 that has come back or has not responded to treatment or high-risk myelodysplastic syndrome that has come back. Pevonedistat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, and 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.
Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the tolerability and feasibility of a MLN4924 (pevonedistat) and azacitidine (pevonedistat [pevo] + azacitidine [aza]) combination added to the standard fludarabine phosphate (fludarabine) and cytarabine re-induction for pediatric patients with recurrent/refractory acute myeloid leukemia (AML) and relapsed 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 relapsed MDS.

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

SECONDARY OBJECTIVES:

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.

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 10-40 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. Cycle 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Blasts 0.1 Percent or More of Bone Marrow Nucleated Cells
  • Recurrent Acute Myeloid Leukemia
  • Recurrent High Risk Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
Intervention  ICMJE
  • Drug: Azacitidine
    Given IV
    Other Names:
    • 5 AZC
    • 5-AC
    • 5-Azacytidine
    • 5-AZC
    • Azacytidine
    • Azacytidine, 5-
    • Ladakamycin
    • Mylosar
    • 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
Study Arms  ICMJE 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 10-40 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. Cycle 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.
Interventions:
  • Drug: Azacitidine
  • Drug: Cytarabine
  • Drug: Fludarabine Phosphate
  • Drug: Methotrexate
  • Drug: Pevonedistat
  • Drug: Therapeutic Hydrocortisone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 21, 2019)
23
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 21, 2020
Estimated Primary Completion Date August 21, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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
  • 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 have received drugs that are moderate to strong inducers of CYP3A4 within 14 days prior to study enrollment are not eligible. Strong inducers of CYP3A4 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Month to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03813147
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Katherine G Tarlock COG Phase I Consortium
PRS Account National Cancer Institute (NCI)
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP