Pevonedistat, Azacitidine, Fludarabine Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
Condition: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic Syndrome; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Syndrome; Recurrence
Study type: Interventional
Phase: Phase 1

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.
    

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.
    

Intervention name(s): Azacitidine; Cytarabine; Fludarabine Phosphate; Methotrexate; Pevonedistat; Therapeutic Hydrocortisone
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Given IV; Given intrathecally and IV; Given IV; Given intrathecally; Given IV; Given intrathecally
Other intervention name(s): 5 AZC; 5-AC; 5-Azacitidine; 5-Azacytidine; 5-AZC; Azacytidine; Azacytidine, 5-; Ladakamycin; Mylosar; U-18496; Vidaza; .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; 2-F-ara-AMP; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Beneflur; Fludara; SH T 586; 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; MLN4924; Nedd8-Activating Enzyme Inhibitor MLN4924; 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
Intervention MeSH terms: Cytarabine; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Methotrexate; Fludarabine phosphate; Azacitidine; Fludarabine; Enzyme Inhibitors; Pevonedistat
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment