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 : September 12, 2019
|Condition or disease||Intervention/treatment||Phase|
|Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Blasts 0.1 Percent or More of Bone Marrow Nucleated Cells Blasts 5 Percent or More of Bone Marrow Nucleated Cells Recurrent Acute Myeloid Leukemia Recurrent High Risk Myelodysplastic Syndrome Refractory Acute Myeloid Leukemia||Drug: Azacitidine Drug: Cytarabine Drug: Fludarabine Phosphate Drug: Methotrexate Drug: Pevonedistat Drug: Therapeutic Hydrocortisone||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||23 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Actual Study Start Date :||May 1, 2019|
|Estimated Primary Completion Date :||August 21, 2020|
|Estimated Study Completion Date :||August 21, 2020|
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.
Given intrathecally and IV
Drug: Fludarabine Phosphate
Drug: Therapeutic Hydrocortisone
- 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).
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03813147
|United States, Alabama|
|Children's Hospital of Alabama||Recruiting|
|Birmingham, Alabama, United States, 35233|
|Contact: Site Public Contact 205-638-9285 email@example.com|
|Principal Investigator: Gregory K. Friedman|
|United States, California|
|Children's Hospital of Orange County||Recruiting|
|Orange, California, United States, 92868|
|Contact: Site Public Contact 714-997-3000|
|Principal Investigator: Josephine H. Haduong|
|United States, District of Columbia|
|Children's National Medical Center||Recruiting|
|Washington, District of Columbia, United States, 20010|
|Contact: Site Public Contact 202-884-2549|
|Principal Investigator: AeRang Kim|
|United States, Georgia|
|Children's Healthcare of Atlanta - Egleston||Recruiting|
|Atlanta, Georgia, United States, 30322|
|Contact: Site Public Contact 404-785-2025 Leann.Schilling@choa.org|
|Principal Investigator: Himalee S. Sabnis|
|United States, Illinois|
|Lurie Children's Hospital-Chicago||Recruiting|
|Chicago, Illinois, United States, 60611|
|Contact: Site Public Contact 773-880-4562|
|Principal Investigator: Joanna L. Weinstein|
|United States, Indiana|
|Riley Hospital for Children||Recruiting|
|Indianapolis, Indiana, United States, 46202|
|Contact: Site Public Contact 800-248-1199|
|Principal Investigator: James M. Croop|
|United States, Minnesota|
|University of Minnesota/Masonic Cancer Center||Recruiting|
|Minneapolis, Minnesota, United States, 55455|
|Contact: Site Public Contact 612-624-2620|
|Principal Investigator: Emily G. Greengard|
|United States, New York|
|NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center||Recruiting|
|New York, New York, United States, 10032|
|Contact: Site Public Contact 212-305-6361 firstname.lastname@example.org|
|Principal Investigator: Alice Lee|
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center||Recruiting|
|Cincinnati, Ohio, United States, 45229|
|Contact: Site Public Contact 513-636-2799 email@example.com|
|Principal Investigator: James I. Geller|
|United States, Pennsylvania|
|Children's Hospital of Philadelphia||Recruiting|
|Philadelphia, Pennsylvania, United States, 19104|
|Contact: Site Public Contact 267-425-5544 CancerTrials@email.chop.edu|
|Principal Investigator: Elizabeth Fox|
|Children's Hospital of Pittsburgh of UPMC||Recruiting|
|Pittsburgh, Pennsylvania, United States, 15224|
|Contact: Site Public Contact 412-692-8570 firstname.lastname@example.org|
|Principal Investigator: Andrew Bukowinski|
|United States, Tennessee|
|St. Jude Children's Research Hospital||Recruiting|
|Memphis, Tennessee, United States, 38105|
|Contact: Site Public Contact 866-278-5833 email@example.com|
|Principal Investigator: Seth E. Karol|
|United States, Texas|
|Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Site Public Contact 713-798-1354 firstname.lastname@example.org|
|Principal Investigator: Jodi Muscal|
|United States, Washington|
|Seattle Children's Hospital||Not yet recruiting|
|Seattle, Washington, United States, 98105|
|Contact: Site Public Contact 866-987-2000|
|Principal Investigator: Julie R. Park|
|Principal Investigator:||Katherine G Tarlock||COG Phase I Consortium|