NCT03813147

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

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 12 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 1 Month – 21 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
• Recurrent Acute Myeloid Leukemia
• Recurrent Myelodysplastic Syndrome
• Refractory Acute Myeloid Leukemia
• Refractory Myelodysplastic Syndrome

Interventions

Type	Name	Description
DRUG	Azacitidine	Given IV
DRUG	Cytarabine	Given intrathecally and IV
DRUG	Fludarabine Phosphate	Given IV
DRUG	Methotrexate	Given intrathecally
DRUG	Pevonedistat	Given IV
DRUG	Therapeutic Hydrocortisone	Given intrathecally

Timeline

• Start date: 2019-05-17
• Primary completion: 2021-09-30
• Completion: 2023-12-31
• First posted: 2019-01-23
• Last updated: 2025-04-13
• Results posted: 2023-03-03

Locations

19 sites across 1 country: United States

Regulatory

• FDA-regulated drug study