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Pevonedistat Plus Azacitidine...

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)

Last Updated: 2025-10-29

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

454 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-11-28

Study Completion Date

2024-10-14

Brief Summary

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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).

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Detailed Description

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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 450 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).

Conditions

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Myelodysplastic Syndrome Leukemia, Myelomonocytic, Chronic Leukemia, Myeloid, Acute

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Azacitidine 75 mg/m^2

Participants were administered azacitidine 75 milligram per square meter (mg/m\^2) intravenous (IV) or subcutaneous (SC) injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Azacitidine intravenous or subcutaneous formulation.

Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2

Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Azacitidine intravenous or subcutaneous formulation.

Pevonedistat

Intervention Type DRUG

Pevonedistat intravenous infusion.

Interventions

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Azacitidine

Azacitidine intravenous or subcutaneous formulation.

Intervention Type DRUG

Pevonedistat

Pevonedistat intravenous infusion.

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. 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).
2. 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.
3. Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2.
4. 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:

* 0 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

1. 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.
2. 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.
3. 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.
4. 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).
5. Has either clinical evidence of or history of central nervous system involvement by AML.
6. Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
7. 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.
8. Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
9. 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.
10. Has known human immunodeficiency virus (HIV) seropositive.
11. 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.
12. Has known hepatic cirrhosis or severe preexisting hepatic impairment.
13. 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.
14. Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the first dose of pevonedistat.

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Medical Director

Role: STUDY_DIRECTOR

Takeda

Locations

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Southern Cancer Center - USOR

Daphne, Alabama, United States

Site Status

Southern Cancer Center - USOR

Mobile, Alabama, United States

Site Status

Southern Cancer Center - USOR

Mobile, Alabama, United States

Site Status

Southern Cancer Center- USOR

Mobile, Alabama, United States

Site Status

Southeastern Regional Medical Center - CTCA - PPDS

Goodyear, Arizona, United States

Site Status

Arizona Oncology Associates (Orange HOPE) - USOR

Tucson, Arizona, United States

Site Status

Arizona Oncology Associates (Rudasill HOPE) - USOR

Tucson, Arizona, United States

Site Status

Arizona Oncology Associates (Wilmot HOPE) - USOR

Tucson, Arizona, United States

Site Status

Compassionate Care Research Group Inc. at Compassionate Cancer Care Medical Group, Inc

Corona, California, United States

Site Status

Compassionate Cancer Care Medical Group Inc

Fountain Valley, California, United States

Site Status

UC San Diego Moores Cancer Center

La Jolla, California, United States

Site Status

Emad Ibrahim, MD, Inc

Redlands, California, United States

Site Status

Compassionate Care Research Group Inc. at Compassionate Cancer Care Medical Group, Inc

Riverside, California, United States

Site Status

Rocky Mountain Cancer Centers (Aurora) - USOR

Aurora, Colorado, United States

Site Status

Rocky Mountain Cancer Centers (Boulder) - USOR

Boulder, Colorado, United States

Site Status