Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS) Chronic Myelomonocytic Leukemia (CMML) or Low-Blast Acute Myelogenous Leukemia (AML)

  • STATUS
    Recruiting
  • End date
    Feb 28, 2025
  • participants needed
    502
  • sponsor
    Millennium Pharmaceuticals, Inc.
Updated on 17 June 2021
Investigator
Takeda Study Registration Call Center
Primary Contact
Hokkaido University Hospital (0.0 mi away) Contact
+319 other location
myeloid leukemia
myelodysplastic syndromes
chronic myelomonocytic leukemia
leukemia
induction chemotherapy
azacitidine
blast cells
myelomonocytic leukemia
pevonedistat

Summary

The purpose of this study is to determine whether the combination of pevonedistat and azacitidine improves event-free survival (EFS) when compared with single-agent azacitidine. (An event is defined as death or transformation to AML in participants with MDS or CMML, whichever occurs first, and is defined as death in participants with low-blast AML).

Description

The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to treat people with higher-risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML) and low-blast acute myelogenous leukemia (AML) as a combination treatment with azacitidine. This study will look at the overall survival, event-free survival and response to treatment in people who take pevonedistat and azacitidine when compared to people who take single-agent azacitidine.

The study will enroll approximately 454 participants. Once enrolled, participants will be randomly assigned in 1:1 ratio (by chance, like flipping a coin) to one of the two treatment groups in 28-day treatment cycles:

  • Pevonedistat 20 mg/m^2 and azacitidine 75 mg/m^2 combination
  • Single-agent azacitidine 75 mg/m^2

All participants will receive azacitidine via intravenous or subcutaneous route. Participants randomized to the combination arm will also receive pevonedistat intravenous infusion.

This multi-center trial will be conducted Spain, Belgium, Brazil, Canada, Czech Republic, France, Germany, Israel, Italy, the United States, Australia, Greece, Japan, Mexico, Poland, Russia, Korea, Turkey, China and United Kingdom. The overall time to participate in this study is approximately 63 months. Participants will attend the end-of-treatment visit 30 days after the last dose of study drug or before the start of subsequent anti-neoplastic therapy if that occurs sooner.

Participants with HR MDS or CMML will have EFS follow-up study visits every month if their disease has not transformed to AML and they have not started subsequent therapy. Participants with low-blast AML will have response follow-up study visits every month until they relapse from CR or meet the criteria for PD. All participants will enter OS follow-up (contacted every 3 months) when they have confirmed transformation to AML (for participants with HR MDS or CMML at enrollment) or experienced PD (for participants with low-blast AML at study enrollment).

Details
Condition Bone marrow disorder, Chronic myelomonocytic leukemia, Preleukemia, Acute myeloid leukemia, MYELODYSPLASTIC SYNDROME, Myelodysplastic Syndromes (MDS), Acute Myelogenous Leukemia (AML), myelodysplastic syndromes, myelodysplastic syndrome (mds)
Treatment Azacitidine, Pevonedistat
Clinical Study IdentifierNCT03268954
SponsorMillennium Pharmaceuticals, Inc.
Last Modified on17 June 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or CMML (i.e., with white blood cell [WBC] <13,000/microliter [mcL]) or low-blast acute myelogenous leukemia (AML)
Has MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R)
Very high (>6 points)
High (>4.5-6 points)
Intermediate (>3-4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts
Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2
Participants with AML (20%-30% blasts) must have a treatment-related mortality (TRM) score >=4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers
Calculation of TRM score
for (age <61 years), +2 for (age 61-70 years), +4 for (age >=71 years)
\+ 0 for (PS=0), +2 for (PS=1), +4 for (PS >1)
\+ 0 for (platelets <50), +1 for (platelets >=50)

Exclusion Criteria

Has previous treatment for HR MDS or CMML or low-blast AML with chemotherapy or other antineoplastic agents including hypomethylating agent (HMAs) such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug
Has acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis
Participants with AML with a WBC count >50,000/mcL. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria
Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a participant is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors
Age >75\
Comorbidities
Inability to tolerate intensive chemotherapy (e.g., participants with AML with 20%-30% blasts and TRM >=4)
Physician decision (e.g., lack of available stem cell donor)
The reason a participant is not eligible should be documented in the electronic case report form (eCRF)
Has either clinical evidence of or history of central nervous system involvement by AML
Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia
Is diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease
Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection
Has prothrombin time (PT) or aPTT >1.5 upper limit of normal (ULN) or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment
Has known human immunodeficiency virus (HIV) seropositive
Has known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Participants 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
Has known hepatic cirrhosis or severe preexisting hepatic impairment
Has known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension
Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the first dose of pevonedistat
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