Last updated on August 2019

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

Brief description of study

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 Study Description


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.


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


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.


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.

Clinical Study Identifier: NCT03813147

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