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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03268954
Registration number
NCT03268954
Ethics application status
Date submitted
30/08/2017
Date registered
31/08/2017
Date last updated
30/04/2024
Titles & IDs
Public title
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)
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Scientific title
A Phase 3, Randomized, Controlled, Open-label, Clinical Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia
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Secondary ID [1]
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2017-000318-40
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Secondary ID [2]
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Pevonedistat-3001
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Universal Trial Number (UTN)
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Trial acronym
PANTHER
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndrome
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Leukemia, Myelomonocytic, Chronic
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Leukemia, Myeloid, Acute
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Blood
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Haematological diseases
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Blood
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Other blood disorders
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Azacitidine
Treatment: Drugs - Pevonedistat
Experimental: Azacitidine 75 mg/m^2 - 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 approximately 42 months.
Experimental: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 - 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 approximately 42 months.
Treatment: Drugs: Azacitidine
Azacitidine intravenous or subcutaneous formulation.
Treatment: Drugs: Pevonedistat
Pevonedistat intravenous infusion.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Event-Free Survival (EFS)
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Assessment method [1]
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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.
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Timepoint [1]
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From randomization until transformation to acute myeloid leukemia, or death due to any cause up to data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [1]
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Overall Survival (OS)
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Assessment method [1]
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Overall survival was defined as the time from randomization to death from any cause.
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Timepoint [1]
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Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [2]
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Kaplan-Meier Estimates of Six-Month Survival Rate
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Assessment method [2]
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Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of Month 6 from randomization are presented.
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Timepoint [2]
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Up to Month 6
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Secondary outcome [3]
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Kaplan-Meier Estimates of One-Year Survival Rate
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Assessment method [3]
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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.
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Timepoint [3]
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Up to Year 1
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Secondary outcome [4]
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Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30
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Assessment method [4]
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30-day mortality was defined as number of participants who died within 30 days from the first dose of study drug.
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Timepoint [4]
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Up to Day 30
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Secondary outcome [5]
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Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60
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Assessment method [5]
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60-day mortality was defined as number of participants who died within 60 days from the first dose of study drug.
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Timepoint [5]
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Up to Day 60
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Secondary outcome [6]
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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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Assessment method [6]
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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%.
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Timepoint [6]
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From randomization until transformation to AML till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [7]
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Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi)
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Assessment method [7]
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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).
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Timepoint [7]
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From randomization until CR till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [8]
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Number of Participants With CR and Marrow CR
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Assessment method [8]
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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.
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Timepoint [8]
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From randomization until CR or marrow CR till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [9]
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Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI)
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Assessment method [9]
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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.
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Timepoint [9]
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From randomization until, CR, PR or HI till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [10]
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Number of Participants With CR and Marrow CR and PR
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Assessment method [10]
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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%.
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Timepoint [10]
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From randomization until CR or Marrow CR and PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [11]
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Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI)
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Assessment method [11]
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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.
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Timepoint [11]
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From randomization until CR, marrow CR, PR or HI till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [12]
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Number of Participants With Overall Response (OR)
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Assessment method [12]
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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.
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Timepoint [12]
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From randomization until CR and PR or CR, CRi and PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [13]
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Number of Participants With Overall Response 2 (OR2)
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Assessment method [13]
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OR2=participant with best overall response of CR+PR+HI in HR MDS/CMML participants,or of CR+CRi+PR in low-blast AML participants.CR:=5% myeloblasts with normal maturation of all bone marrow(BM)cell lines,=11g/dL Hgb,=100*10^9/L pl,=1.0*10^9/L neutrophils,0% blasts in peripheral blood;PR:all CR criteria met except BM blasts =50% decrease over pretreatment but still >5%;HI:Hgb increase(inc) =1.5g/dL if baseline(BL)<11 g/dL;pl inc=30*10^9/L if BL>20*10^9/L or inc from <20*10^9/L to >20*10^9/L and by 100%;neutrophil inc by 100%;absolute inc of >0.5*10^9/L if BL<100*10^9/L.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: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 BM aspirate.Number of responders determined by independent review committee(IRC) assessment.
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Timepoint [13]
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From randomization until, CR, PR or HI or CR, CRi or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [14]
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Duration of Complete Remission (CR)
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Assessment method [14]
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Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML) or relapse after CR or PR (participants with HR MDS/CMML). Disease responses for HR MDS or CMML are based on the Modified IWG Response Criteria for MDS and for low-blast AML on the Revised IWG Response Criteria for AML. 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 g/dL Hgb,>=100*10^9/L 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).
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Timepoint [14]
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From CR until first documentation of PD or relapse from CR or relapse after CR or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [15]
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Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi)
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Assessment method [15]
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Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML). Disease responses for low-blast AML were based on the Revised IWG Response Criteria for AML. CR is defined as <=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to >=11 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).
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Timepoint [15]
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From CR until first documentation of PD or relapse from CR or relapse after CR or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [16]
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Duration of Overall Response (OR)
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Assessment method [16]
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Duration of OR: response to first documentation of PD or relapse from CR for low-blast AML or relapse after CR or PR for HR MDS/CMML. 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+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 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 % of blasts in bone marrow aspirate.
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Timepoint [16]
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Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [17]
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Duration of Overall Response 2 (OR2)
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Assessment method [17]
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Duration of OR2: from date of first documentation of CR+PR+HI to first documentation of PD/relapse after CR/PR for responders of CR+PR+HI for HR MDS/CMML and CR,CRi,PR for low-blast AML. For HR MDS/CMML-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; PR: all CR criteria met except bone marrow blasts>=50% decrease over pretreatment, still >5%; HI:Hgb inc >=1.5 g/dL if baseline <11 g/dL; pl inc>=30*10^9/L if baseline>20*10^9/L or inc from<20*10^9/L to>20*10^9/L by at least 100%; neutrophil inc by 100% and absolute inc of >0.5*10^9/L if baseline <1.0*10^9/L.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;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.
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Timepoint [17]
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Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [18]
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Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence
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Assessment method [18]
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A participant was defined as RBC or platelet-transfusion independent if he/she received no RBC or platelet transfusions for a period of at least 8 weeks before the first dose of study drug through 30 days after the last dose of any study drug. Rate of transfusion independence was defined as number of participants who became transfusion independent divided by the number of participants who were transfusion dependent at Baseline.
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Timepoint [18]
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Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [19]
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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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Assessment method [19]
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Duration of RBC and platelet transfusion independence was defined as the longest time between the last RBC and/or platelet transfusion before the start of the RBC and/or platelet transfusion-independent period and the first RBC and/or platelet transfusion after the start of the transfusion-independent period, which occurs >= 8 weeks later.
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Timepoint [19]
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Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [20]
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Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi)
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Assessment method [20]
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Time to first CR or PR is defined as the time from randomization to first documented CR or PR, whichever occurs first. Disease responses for HR MDS or CMML or low-blast AML cycle 6 are based on Modified IWG Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. For HR MDS or CMML-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; 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/L neutrophils, pl>=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery: fulfill CR criteria except residual neutropenia<1.0*10^9/L or pl <100*10^9/L; PR: all CR hematological values but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate.
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Timepoint [20]
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From randomization until CR or PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [21]
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Number of Participants With Hematologic Improvement (HI)
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Assessment method [21]
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Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. 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 increase from <20*10^9/L to >20*10^9/L by at least 100%; neutrophil increase by 100% and absolute increase of >0.5*10^9/L if baseline <1.0*10^9/L.
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Timepoint [21]
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From randomization until HI till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [22]
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Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML
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Assessment method [22]
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Inpatient hospital admission data was collected through transformation to AML (HR MDS/CMML participants) or disease progression (low-blast AML participants) or until initiation of subsequent therapy (all participants), whichever occurred first. Transformation to AML is defined, according to WHO Classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%.
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Timepoint [22]
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From randomization until transformation to AML or until initiation of subsequent therapy till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [23]
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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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Assessment method [23]
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Time to PD, relapse after CR(low-blast AML), relapse after CR or PR(HR MDS/CMML), or death,defined as time from date of randomization until date of first documentation of PD,relapse after CR(low-blast AML),relapse after CR or PR(HR MDS/CMML),or death due to any cause, whichever occurs first. In HR MDS/CMML,PD: Participants with<5% blasts:>=50% inc >5% blasts, with 5%-9% blasts:>=50% inc>10% blasts, with 10%-19% blasts:>=50% inc >20% blasts,with 20%-30% blasts, at least 50% decrement from maximum remission/response in granulocytes or pl or reduction in Hgb by>=2 g/dL/new transfusion dependence.Relapse after CR or PR: return to pretreatment bone marrow blast %/Decrement of >=50% from maximum remission/response levels in granulocytes/pl/reduction in Hgb conc.>=1.5 g/dL/transfusion dependence. In AML,PD:>50% inc in bone marrow blasts to >30% blasts,>50% inc in circulating blasts to>30% blasts in peripheral blood, Development of extramedullary disease/new sites of extramedullary leukemia.
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Timepoint [23]
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From randomization until PD, relapse after CR, or relapse after CR or PR, or death due to any cause, whichever occurs first till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [24]
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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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Assessment method [24]
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The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. Most of the 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QOL scale, higher scores represent better QOL; for the symptom scales, lower scores represent better QOL. The percentage of participants for each parameter score were categorized as improved, stable, and worsened. Only categories with at least one participant with event are reported.
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Timepoint [24]
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Up to data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [25]
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Plasma Concentration of Pevonedistat
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Assessment method [25]
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Timepoint [25]
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Cycle 1 Day 1 predose and multiple time points (up to 4 hours) post dose; Cycle 1 Days 3 and 5 predose; Cycle 2 and 4 Day 1 at multiple time points (up to 3 hours) post dose; Cycle 4 Day 3 predose (Cycle length= 28 days)
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Secondary outcome [26]
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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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Assessment method [26]
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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 + 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 the percentage of blasts to 5% to 25% in bone marrow aspirate.
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Timepoint [26]
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From randomization until CR, CRi and PR till data cut-off date: 28 May 2021 (up to approximately 42 months)
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Secondary outcome [27]
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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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Assessment method [27]
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Event was defined as death or transformation to AML in participants with MDS or CMML, whichever occurred first. Transformation to AML was defined, according to World Health Organization (WHO) Classification as a participant having >20% blasts in the blood or marrow and increase of blast count by 50%. Event was defined as death in participants with low-blast AML.
Query!
Timepoint [27]
0
0
From randomization until transformation to AML if eligible or death till data cut-off date: 28 May 2021 (up to approximately 42 months)
Query!
Secondary outcome [28]
0
0
Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group
Query!
Assessment method [28]
0
0
OS was calculated from date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis were censored as of the date the participant was last known to be alive.
Query!
Timepoint [28]
0
0
From randomization until death till data cut-off date: 28 May 2021 (up to approximately 42 months)
Query!
Secondary outcome [29]
0
0
Number of Participants With Overall Response by Cycle 6
Query!
Assessment method [29]
0
0
Responses for HR MDS/CMML are based on Modified International Working Group (IWG) Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR and PR for HR MDS/CMML and CR+CR with incomplete blood count recovery(CRi)+PR for low-blast AML. CR for HR MDS/CMML:<=5% myeloblasts with normal maturation of all bone marrow cell lines,>=11g/dL hemoglobin (Hgb),>=100*10^9/L platelet (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;CRi:fulfill CR criteria except residual neutropenia <1.0*10^9/L/thrombocytopenia (pl<100*10^9/L); PR:all CR hematological values but>=50% decrease in percentage of blasts to 5%-25% in bone marrow aspirate.
Query!
Timepoint [29]
0
0
Up to Cycle 6 (up to approximately Day 168)
Query!
Eligibility
Key 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).
Query!
Minimum age
18
Years
Query!
Query!
Maximum age
No limit
Query!
Query!
Sex
Both males and females
Query!
Can healthy volunteers participate?
No
Query!
Key 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.
Query!
Study design
Purpose of the study
Treatment
Query!
Allocation to intervention
Randomised controlled trial
Query!
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Query!
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Query!
Masking / blinding
Open (masking not used)
Query!
Who is / are masked / blinded?
Query!
Query!
Query!
Query!
Intervention assignment
Parallel
Query!
Other design features
Query!
Phase
Phase 3
Query!
Type of endpoint/s
Query!
Statistical methods / analysis
Query!
Recruitment
Recruitment status
Active, not recruiting
Query!
Data analysis
Query!
Reason for early stopping/withdrawal
Query!
Other reasons
Query!
Date of first participant enrolment
Anticipated
Query!
Actual
28/11/2017
Query!
Date of last participant enrolment
Anticipated
Query!
Actual
Query!
Date of last data collection
Anticipated
30/06/2024
Query!
Actual
Query!
Sample size
Target
Query!
Accrual to date
Query!
Final
454
Query!
Recruitment in Australia
Recruitment state(s)
QLD,TAS
Query!
Recruitment hospital [1]
0
0
Icon Cancer Care Wesley - Auchenflower
Query!
Recruitment hospital [2]
0
0
Icon Cancer Care Chermside - Chermside
Query!
Recruitment hospital [3]
0
0
Icon Cancer Care South Brisbane - South Brisbane
Query!
Recruitment hospital [4]
0
0
Icon Cancer Care - South Brisbane
Query!
Recruitment hospital [5]
0
0
Icon Cancer Care Southport - Southport
Query!
Recruitment hospital [6]
0
0
Royal Hobart Hospital - Hobart
Query!
Recruitment hospital [7]
0
0
Liverpool Hospital - Liverpool
Query!
Recruitment postcode(s) [1]
0
0
4066 - Auchenflower
Query!
Recruitment postcode(s) [2]
0
0
4032 - Chermside
Query!
Recruitment postcode(s) [3]
0
0
4101 - South Brisbane
Query!
Recruitment postcode(s) [4]
0
0
4215 - Southport
Query!
Recruitment postcode(s) [5]
0
0
7000 - Hobart
Query!
Recruitment postcode(s) [6]
0
0
1871 - Liverpool
Query!
Recruitment outside Australia
Country [1]
0
0
United States of America
Query!
State/province [1]
0
0
Alabama
Query!
Country [2]
0
0
United States of America
Query!
State/province [2]
0
0
Arizona
Query!
Country [3]
0
0
United States of America
Query!
State/province [3]
0
0
California
Query!
Country [4]
0
0
United States of America
Query!
State/province [4]
0
0
Colorado
Query!
Country [5]
0
0
United States of America
Query!
State/province [5]
0
0
District of Columbia
Query!
Country [6]
0
0
United States of America
Query!
State/province [6]
0
0
Florida
Query!
Country [7]
0
0
United States of America
Query!
State/province [7]
0
0
Georgia
Query!
Country [8]
0
0
United States of America
Query!
State/province [8]
0
0
Idaho
Query!
Country [9]
0
0
United States of America
Query!
State/province [9]
0
0
Illinois
Query!
Country [10]
0
0
United States of America
Query!
State/province [10]
0
0
Kansas
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Country [11]
0
0
United States of America
Query!
State/province [11]
0
0
Missouri
Query!
Country [12]
0
0
United States of America
Query!
State/province [12]
0
0
Nebraska
Query!
Country [13]
0
0
United States of America
Query!
State/province [13]
0
0
New Jersey
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Country [14]
0
0
United States of America
Query!
State/province [14]
0
0
New York
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Country [15]
0
0
United States of America
Query!
State/province [15]
0
0
North Carolina
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Country [16]
0
0
United States of America
Query!
State/province [16]
0
0
Ohio
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Country [17]
0
0
United States of America
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State/province [17]
0
0
Pennsylvania
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Country [18]
0
0
United States of America
Query!
State/province [18]
0
0
South Carolina
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Country [19]
0
0
United States of America
Query!
State/province [19]
0
0
Tennessee
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Country [20]
0
0
United States of America
Query!
State/province [20]
0
0
Texas
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Country [21]
0
0
United States of America
Query!
State/province [21]
0
0
Virginia
Query!
Country [22]
0
0
Belgium
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State/province [22]
0
0
Antwerpen
Query!
Country [23]
0
0
Belgium
Query!
State/province [23]
0
0
Namur
Query!
Country [24]
0
0
Belgium
Query!
State/province [24]
0
0
West-Vlaanderen
Query!
Country [25]
0
0
Belgium
Query!
State/province [25]
0
0
Bruxelles
Query!
Country [26]
0
0
Belgium
Query!
State/province [26]
0
0
Leuven
Query!
Country [27]
0
0
Brazil
Query!
State/province [27]
0
0
Parana
Query!
Country [28]
0
0
Brazil
Query!
State/province [28]
0
0
Rio Grande Do Norte
Query!
Country [29]
0
0
Brazil
Query!
State/province [29]
0
0
Santa Catarina
Query!
Country [30]
0
0
Brazil
Query!
State/province [30]
0
0
Porto Alegre
Query!
Country [31]
0
0
Brazil
Query!
State/province [31]
0
0
Rio De Janeiro
Query!
Country [32]
0
0
Brazil
Query!
State/province [32]
0
0
Sao Paulo
Query!
Country [33]
0
0
Canada
Query!
State/province [33]
0
0
Alberta
Query!
Country [34]
0
0
Canada
Query!
State/province [34]
0
0
New Brunswick
Query!
Country [35]
0
0
Canada
Query!
State/province [35]
0
0
Ontario
Query!
Country [36]
0
0
China
Query!
State/province [36]
0
0
Beijing
Query!
Country [37]
0
0
China
Query!
State/province [37]
0
0
Tianjin
Query!
Country [38]
0
0
Czechia
Query!
State/province [38]
0
0
Kralovehradeck Kraj
Query!
Country [39]
0
0
Czechia
Query!
State/province [39]
0
0
Prague
Query!
Country [40]
0
0
Czechia
Query!
State/province [40]
0
0
Praha
Query!
Country [41]
0
0
France
Query!
State/province [41]
0
0
Calvados
Query!
Country [42]
0
0
France
Query!
State/province [42]
0
0
Maine-et-Loire
Query!
Country [43]
0
0
France
Query!
State/province [43]
0
0
Le Mans
Query!
Country [44]
0
0
France
Query!
State/province [44]
0
0
Paris
Query!
Country [45]
0
0
Germany
Query!
State/province [45]
0
0
Baden-Wurttemberg
Query!
Country [46]
0
0
Germany
Query!
State/province [46]
0
0
Sachsen
Query!
Country [47]
0
0
Germany
Query!
State/province [47]
0
0
Dresden
Query!
Country [48]
0
0
Germany
Query!
State/province [48]
0
0
Dusseldorf
Query!
Country [49]
0
0
Greece
Query!
State/province [49]
0
0
Attiki
Query!
Country [50]
0
0
Greece
Query!
State/province [50]
0
0
Alexandroupolis
Query!
Country [51]
0
0
Greece
Query!
State/province [51]
0
0
Athens
Query!
Country [52]
0
0
Greece
Query!
State/province [52]
0
0
Ioannina
Query!
Country [53]
0
0
Greece
Query!
State/province [53]
0
0
Larissa
Query!
Country [54]
0
0
Greece
Query!
State/province [54]
0
0
Patras
Query!
Country [55]
0
0
Greece
Query!
State/province [55]
0
0
Thessaloniki
Query!
Country [56]
0
0
Israel
Query!
State/province [56]
0
0
Holon
Query!
Country [57]
0
0
Israel
Query!
State/province [57]
0
0
Jerusalem
Query!
Country [58]
0
0
Israel
Query!
State/province [58]
0
0
Nahariya
Query!
Country [59]
0
0
Israel
Query!
State/province [59]
0
0
Safed
Query!
Country [60]
0
0
Israel
Query!
State/province [60]
0
0
Tel Aviv
Query!
Country [61]
0
0
Italy
Query!
State/province [61]
0
0
Emilia-Romagna
Query!
Country [62]
0
0
Italy
Query!
State/province [62]
0
0
Lombardia
Query!
Country [63]
0
0
Italy
Query!
State/province [63]
0
0
Firenze
Query!
Country [64]
0
0
Italy
Query!
State/province [64]
0
0
Rionero in Vulture
Query!
Country [65]
0
0
Italy
Query!
State/province [65]
0
0
Rozzano
Query!
Country [66]
0
0
Italy
Query!
State/province [66]
0
0
Torino
Query!
Country [67]
0
0
Japan
Query!
State/province [67]
0
0
Hirosima
Query!
Country [68]
0
0
Japan
Query!
State/province [68]
0
0
Hokkaido
Query!
Country [69]
0
0
Japan
Query!
State/province [69]
0
0
Hukusima
Query!
Country [70]
0
0
Japan
Query!
State/province [70]
0
0
Hyogo
Query!
Country [71]
0
0
Japan
Query!
State/province [71]
0
0
Kyoto
Query!
Country [72]
0
0
Japan
Query!
State/province [72]
0
0
Osaka
Query!
Country [73]
0
0
Japan
Query!
State/province [73]
0
0
Saitama
Query!
Country [74]
0
0
Japan
Query!
State/province [74]
0
0
Tokyo
Query!
Country [75]
0
0
Japan
Query!
State/province [75]
0
0
Fukuoka-city
Query!
Country [76]
0
0
Japan
Query!
State/province [76]
0
0
Mibu
Query!
Country [77]
0
0
Japan
Query!
State/province [77]
0
0
Nagasaki
Query!
Country [78]
0
0
Japan
Query!
State/province [78]
0
0
Yokohama-shi
Query!
Country [79]
0
0
Japan
Query!
State/province [79]
0
0
Yoshida-gun
Query!
Country [80]
0
0
Korea, Republic of
Query!
State/province [80]
0
0
Busan
Query!
Country [81]
0
0
Korea, Republic of
Query!
State/province [81]
0
0
Daegu
Query!
Country [82]
0
0
Korea, Republic of
Query!
State/province [82]
0
0
Jeongnam
Query!
Country [83]
0
0
Korea, Republic of
Query!
State/province [83]
0
0
Seoul
Query!
Country [84]
0
0
Mexico
Query!
State/province [84]
0
0
Huixquilucan
Query!
Country [85]
0
0
Mexico
Query!
State/province [85]
0
0
Mexico
Query!
Country [86]
0
0
Poland
Query!
State/province [86]
0
0
Mazowieckie
Query!
Country [87]
0
0
Poland
Query!
State/province [87]
0
0
Pomorskie
Query!
Country [88]
0
0
Poland
Query!
State/province [88]
0
0
Swietokrzyskie
Query!
Country [89]
0
0
Poland
Query!
State/province [89]
0
0
Lublin
Query!
Country [90]
0
0
Poland
Query!
State/province [90]
0
0
Opole
Query!
Country [91]
0
0
Russian Federation
Query!
State/province [91]
0
0
Moscow
Query!
Country [92]
0
0
Russian Federation
Query!
State/province [92]
0
0
Saint Petersburg
Query!
Country [93]
0
0
Russian Federation
Query!
State/province [93]
0
0
St. Petersburg
Query!
Country [94]
0
0
Spain
Query!
State/province [94]
0
0
Barcelona
Query!
Country [95]
0
0
Spain
Query!
State/province [95]
0
0
Castilla Y Leon
Query!
Country [96]
0
0
Spain
Query!
State/province [96]
0
0
Madrid
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Country [97]
0
0
Spain
Query!
State/province [97]
0
0
Salamanca
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Country [98]
0
0
Spain
Query!
State/province [98]
0
0
Valencia
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Country [99]
0
0
Turkey
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State/province [99]
0
0
Ankara
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Country [100]
0
0
Turkey
Query!
State/province [100]
0
0
Izmir
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Country [101]
0
0
Turkey
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State/province [101]
0
0
Mersin
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Country [102]
0
0
Turkey
Query!
State/province [102]
0
0
Samsun
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Country [103]
0
0
Turkey
Query!
State/province [103]
0
0
Tekirdag
Query!
Country [104]
0
0
Turkey
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State/province [104]
0
0
Trabzon
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Country [105]
0
0
United Kingdom
Query!
State/province [105]
0
0
Dorset
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Country [106]
0
0
United Kingdom
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State/province [106]
0
0
Kent
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Country [107]
0
0
United Kingdom
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State/province [107]
0
0
London
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Country [108]
0
0
United Kingdom
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State/province [108]
0
0
Swansea
Query!
Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Query!
Name
Takeda
Query!
Address
Query!
Country
Query!
Other collaborator category [1]
0
0
Commercial sector/Industry
Query!
Name [1]
0
0
Takeda Development Center Americas, Inc.
Query!
Address [1]
0
0
Query!
Country [1]
0
0
Query!
Ethics approval
Ethics application status
Query!
Summary
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).
Query!
Trial website
https://clinicaltrials.gov/ct2/show/NCT03268954
Query!
Trial related presentations / publications
Query!
Public notes
Query!
Contacts
Principal investigator
Name
0
0
Medical Director
Query!
Address
0
0
Takeda
Query!
Country
0
0
Query!
Phone
0
0
Query!
Fax
0
0
Query!
Email
0
0
Query!
Contact person for public queries
Name
0
0
Query!
Address
0
0
Query!
Country
0
0
Query!
Phone
0
0
Query!
Fax
0
0
Query!
Email
0
0
Query!
Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03268954
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