NCT03268954 · REGISTRY CONDITION SEARCH

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)

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2025-10-29

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).

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Event-Free Survival (EFS)

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

Kaplan-Meier Estimates of Six-Month Survival Rate

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outcome · POSTED

Kaplan-Meier Estimates of One-Year Survival Rate

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outcome · POSTED

Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30

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outcome · POSTED

Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60

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outcome · POSTED

Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants

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outcome · POSTED

Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi)

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outcome · POSTED

Number of Participants With CR and Marrow CR

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outcome · POSTED

Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI)

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outcome · POSTED

Number of Participants With CR and Marrow CR and PR

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outcome · POSTED

Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI)

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outcome · POSTED

Number of Participants With Overall Response (OR)

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outcome · POSTED

Number of Participants With Overall Response 2 (OR2)

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outcome · POSTED

Duration of Complete Remission (CR)

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outcome · POSTED

Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi)

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outcome · POSTED

Duration of Overall Response (OR)

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outcome · POSTED

Duration of Overall Response 2 (OR2)

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outcome · POSTED

Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence

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outcome · POSTED

Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence

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outcome · POSTED

Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi)

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outcome · POSTED

Number of Participants With Hematologic Improvement (HI)

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outcome · POSTED

Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML

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outcome · POSTED

Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death

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outcome · POSTED

Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30

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outcome · POSTED

Number of Participants With Overall Response in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

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outcome · POSTED

Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

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outcome · POSTED

Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

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outcome · POSTED

Number of Participants With Overall Response by Cycle 6

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: 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.
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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.
intervention Names
Drug: Azacitidine
label
Azacitidine 75 mg/m^2
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Azacitidine
Drug: Pevonedistat
label
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
type
EXPERIMENTAL

interventions

arm Group Labels
Azacitidine 75 mg/m^2
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
description
Azacitidine intravenous or subcutaneous formulation.
name
Azacitidine
type
DRUG
arm Group Labels
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
description
Pevonedistat intravenous infusion.
name
Pevonedistat
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 454
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
EFS was defined as the time from randomization to the date of an EFS event. An EFS event was defined as death or transformation to acute myelogenous leukemia (AML) (World Health Organization \[WHO\] classification as a participant having greater than 20 % blasts in the blood or marrow and an increase of blast count by 50%), whichever event occurred first, in participants with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemias (CMML). An EFS event was defined as death in participants with low-blast AML.
measure
Event-Free Survival (EFS)
time Frame
From randomization until transformation to acute myeloid leukemia, or death due to any cause: up to approximately 42 months

secondary Outcomes

description
Overall survival was defined as the time from randomization to death from any cause.
measure
Overall Survival (OS)
time Frame
Up to approximately 6.9 years
description
Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of Month 6 from randomization are presented.
measure
Kaplan-Meier Estimates of Six-Month Survival Rate
time Frame
Month 6
description
Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of the first year from randomization are presented.
measure
Kaplan-Meier Estimates of One-Year Survival Rate
time Frame
Year 1
description
30-day mortality was defined as number of participants who died within 30 days from the first dose of study drug.
measure
Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30
time Frame
Up to Day 30
description
60-day mortality was defined as number of participants who died within 60 days from the first dose of study drug.
measure
Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60
time Frame
Up to Day 60
description
Time to AML transformation in HR MDS and CMML participants was defined as time from randomization to documented AML transformation as determined by the independent review committee (IRC) assessment. Participants who died before progression to AML were censored. Transformation to AML was defined, according to WHO classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%.
measure
Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants
time Frame
From randomization until transformation to AML (up to approximately 42 months)
description
CR for HR MDS or CMML is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to \>=11 gram per deciliter (g/dL) hemoglobin (Hgb),\>=100\*10\^9/liter (/L) platelets (pl),\>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0\*10\^9/L and pl of \>=100\*10\^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (\<1.0\*10\^9/L) or thrombocytopenia (pl\<100\*10\^9/L).
measure
Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi)
time Frame
From randomization until CR (up to approximately 42 months)
description
Disease responses for HR MDS or CMML are based on the International Working Group (IWG) Response Criteria for MDS. CR for HR MDS or CMML is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and \>=11 g/dL Hgb, \>=100\*10\^9/L platelets (pl), \>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment.
measure
Number of Participants With CR and Marrow CR
time Frame
From randomization until CR or marrow CR (up to approximately 42 months)
description
Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment. PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still \>5%. HI: Hgb increase \>=1.5 g/dL if \<11 g/dL; pl increase \>=30\*10\^9/L if baseline\>20\*10\^9/L or increase from \<20\*10\^9/L to \>20\*10\^9/L and by at least 100%; neutrophil increase by 100% and absolute increase of \>0.5\*10\^9/L if baseline \<1.0\*10\^9/L.
measure
Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI)
time Frame
From randomization until, CR, PR or HI (up to approximately 42 months)
description
Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment. PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still \>5%.
measure
Number of Participants With CR and Marrow CR and PR
time Frame
From randomization until CR or Marrow CR and PR (up to approximately 42 months)
description
Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment. PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still\>5%. HI: Hgb increase \>=1.5 g/dL if baseline \<11 g/dL; pl increase \>=30\*10\^9/L if baseline\>20\*10\^9/L or increases from \<20\*10\^9/L to \>20\*10\^9/L and by at least 100%; neutrophil increases by 100% and absolute increases of \>0.5\*10\^9/L if baseline \<1.0\*10\^9/L.
measure
Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI)
time Frame
From randomization until CR, marrow CR, PR or HI (up to approximately 42 months)
description
Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR or PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still\>5%. For low-blast AML-CR:morphologic leukemia-free state\>1.0\*10\^9 neutrophils, \>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L or pl \<100\*10\^9/L; PR: all CR hematological values but \>=50% decrease in bone marrow aspirate.
measure
Number of Participants With Overall Response (OR)
time Frame
From randomization until CR and PR or CR, CRi and PR (up to approximately 42 months)

Full study description

brief 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).
detailed 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 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).

Source references

references

citation
Ades L, Girshova L, Doronin VA, Diez-Campelo M, Valcarcel D, Kambhampati S, Viniou NA, Woszczyk D, De Paz Arias R, Symeonidis A, Anagnostopoulos A, Munhoz EC, Platzbecker U, Santini V, Fram RJ, Yuan Y, Friedlander S, Faller DV, Sekeres MA. Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML. Blood Adv. 2022 Sep 13;6(17):5132-5145. doi: 10.1182/bloodadvances.2022007334.
pmid
35728048
type
DERIVED