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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03268954




Registration number
NCT03268954
Ethics application status
Date submitted
30/08/2017
Date registered
31/08/2017
Date last updated
19/06/2020

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)
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
Secondary ID [1] 0 0
2017-000318-40
Secondary ID [2] 0 0
Pevonedistat-3001
Universal Trial Number (UTN)
Trial acronym
PANTHER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndrome 0 0
Leukemia, Myelomonocytic, Chronic 0 0
Leukemia, Myeloid, Acute 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Azacitidine
Treatment: Drugs - Pevonedistat

Experimental: Azacitidine + Pevonedistat - Azacitidine 75 milligram per square meter (mg/m^2), intravenous or subcutaneous, on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m^2, 60-minute (+/-10) infusion, intravenous, on Days 1, 3, and 5 in 28-day treatment cycles up to 12 cycles.

Experimental: Azacitidine - Azacitidine 75 mg/m^2, intravenous or subcutaneous, on Days 1 to 5, Days 8 and 9 in 28-day treatment cycles up to 9 cycles.


Treatment: Drugs: Azacitidine
Azacitidine intravenous or subcutaneous formulation.

Treatment: Drugs: Pevonedistat
Pevonedistat intravenous infusion.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-Free Survival (EFS) - EFS is defined as the time from randomization to the date of an EFS event. An EFS event is defined as death or transformation to AML (World Health Organization [WHO] classification as a participant having greater than (>) 20 percent (%) blasts in the blood or marrow and an increase of blast count by 50%), whichever event occurs first, in participants with MDS or CMML. An EFS event is defined as death in participants with low-blast AML.
Timepoint [1] 0 0
From randomization until transformation to acute myeloid leukemia, or death due to any cause : up to 6 years
Secondary outcome [1] 0 0
Overall Survival (OS) - OS is calculated as the time from date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis will be censored as of the date the participant was last known to be alive.
Timepoint [1] 0 0
From randomization until death : up to 6 years
Secondary outcome [2] 0 0
Six-Month Survival Rate - Six-month survival rate is defined as Kaplan-Meier estimate of six-month survival rate.
Timepoint [2] 0 0
Month 6
Secondary outcome [3] 0 0
One-Year Survival Rate - One-year survival rate is defined as Kaplan-Meier estimate of one-year survival rate.
Timepoint [3] 0 0
Month 12
Secondary outcome [4] 0 0
Thirty-Day Survival Rate - Thirty-day survival rate is defined as Kaplan-Meier estimate of thirty-day survival rate.
Timepoint [4] 0 0
Day 30
Secondary outcome [5] 0 0
Sixty-Day Survival Rate - Sixty-day survival rate is defined as Kaplan-Meier estimate of sixty-day survival rate.
Timepoint [5] 0 0
Day 60
Secondary outcome [6] 0 0
Time to AML Transformation in HR MDS and CMML Participants - Time to AML transformation in HR MDS and CMML participants is defined as time from randomization to documented AML transformation. Participants who died before progression to AML will be censored. 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%.
Timepoint [6] 0 0
From randomization until transformation to AML : up to 6 years
Secondary outcome [7] 0 0
Percentage of Participants with complete remission (CR) and complete remission with incomplete blood count recovery (CRi) - Disease responses for HR MDS or CMML or low-blast AML are based on the Modified IWG Response Criteria for MDS and for low-blast AML on the Revised International Working Group (IWG) Response Criteria for AML. CR for HR MDS or CMML is defined as less than or equal to (<=) 5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to (>=)11 grams per deciliter (g/dL) Hemoglobin (Hgb), >=100*10^9 per 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 >1.0*10^9/L and pl of >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CRi for low-blast AML is based on the Modified IWG Response Criteria for low-blast AML. Patients fulfill all the criteria for CR except for less than (<)1.0*10^9 per liter (/L) neutrophils and less than (<)1.0*10^9/L platelets).
Timepoint [7] 0 0
From randomization until CR and CRi : up to 6 years
Secondary outcome [8] 0 0
Percentage of Participants with CR and Marrow CR - Disease responses for HR MDS or CMML are based on the 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 >=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.
Timepoint [8] 0 0
From randomization until CR or marrow CR : up to 6 years
Secondary outcome [9] 0 0
Percentage of Participants with CR, partial remission (PR) and Hematologic Improvement (HI) - 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 (inc) >=1.5 g/dL if baseline less than (<)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 and by at least 100%; neutrophil inc by 100% and absolute inc of >0.5*10^9/L if baseline <1.0*10^9/L.
Timepoint [9] 0 0
From randomization until, CR, PR or HI : up to 6 years
Secondary outcome [10] 0 0
Percentage of Participants with CR and Marrow CR and PR - 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%.
Timepoint [10] 0 0
From randomization until CR or Marrow CR and PR : up to 6 years
Secondary outcome [11] 0 0
Percentage of Participants with CR and Marrow CR, PR and Hematologic Improvement (HI) - 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 (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 and by at least 100%; neutrophil inc by 100% and absolute inc of >0.5*10^9/L if baseline <1.0*10^9/L.
Timepoint [11] 0 0
From randomization until CR, marrow CR, PR or HI : up to 6 years
Secondary outcome [12] 0 0
Percentage of Participants with Overall Response (OR) - 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.
Timepoint [12] 0 0
From randomization until CR and PR or CR, CRi and PR : up to 6 years
Secondary outcome [13] 0 0
Percentage of Participants with Overall Response 2 (OR2) - Overall response 2=CR, PR or HI for HR MDS/CMML and CR, CRi or 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 but still >5%;HI: Hgb increase (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 and by 100%; and neutrophil inc by 100% and absolute inc of >0.5*10^9/L if baseline <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 bone marrow aspirate.
Timepoint [13] 0 0
From randomization until, CR, PR or HI or CR, CRi or PR : up to 6 years
Secondary outcome [14] 0 0
Duration of CR - 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 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).
Timepoint [14] 0 0
From CR until first documentation of PD or relapse from CR or relapse after CR or PR : up to 6 years
Secondary outcome [15] 0 0
Duration of Overall Response (OR) - 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.
Timepoint [15] 0 0
From CR or PR or CR, CRi or PR to the first documented PD or relapse from CR (in participants with low-blast AML) or relapse after CR or PR (in participants with HR MDS/CMML): up to 6 years
Secondary outcome [16] 0 0
Duration of Overall Response 2 (OR2) - Duration of OR2:response to first documented PD or relapse from CR for low-blast AML or relapse after CR or PR for HR MDS/CMML.OR2=CR,PR,HI for 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
Timepoint [16] 0 0
From documented CR, PR or HI to the first documented PD or relapse from CR (in participants with low-blast AML) or relapse after CR or PR (in participants with HR MDS/CMML): up to 6 years
Secondary outcome [17] 0 0
Percentage of Participants with Red Blood Cells (RBCs) and Platelet-transfusion Independence - A participant is defined as RBC or platelet-transfusion independent if he/she receives 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 is defined as number of participants who become transfusion independent divided by the number of participants who are transfusion dependent at Baseline.
Timepoint [17] 0 0
8 weeks before the first dose of study drug through 30 days after last dose of any study drug : up to 6 years
Secondary outcome [18] 0 0
Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence - Duration of RBC and Platelet transfusion independence is 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.
Timepoint [18] 0 0
8 weeks before the first dose of study drug through 30 days after last dose of any study drug : up to 6 years
Secondary outcome [19] 0 0
Time to First CR or PR - 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.
Timepoint [19] 0 0
From randomization until CR or PR : up to 6 years
Secondary outcome [20] 0 0
Percentage of Participants with Hematologic Improvement (HI) - Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. HI: Hgb increase (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.
Timepoint [20] 0 0
From randomization until HI : up to 6 years
Secondary outcome [21] 0 0
Percentage of Participants with at least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML - Inpatient hospital admission data will be 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 occurs 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%.
Timepoint [21] 0 0
From randomization until transformation to AML or until initiation of subsequent therapy up to approximately up to 6 years
Secondary outcome [22] 0 0
Time to Progressive Disease (PD), Relapse after CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death - 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.
Timepoint [22] 0 0
From randomization until PD, relapse after CR, or relapse after CR or PR, or death due to any cause, whichever occurs first (up to 6 years)
Secondary outcome [23] 0 0
Health-Related Quality of Life (HRQOL) using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 - 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.
Timepoint [23] 0 0
Baseline Up to 6 years
Secondary outcome [24] 0 0
Plasma Concentration of Pevonedistat
Timepoint [24] 0 0
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
Secondary outcome [25] 0 0
Percentage 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 - 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.
Timepoint [25] 0 0
From randomization until CR, CRi and PR : up to 6 years
Secondary outcome [26] 0 0
Event-Free Survival in Participants who have TP53 Mutations, 17p Deletions, and/or are Determined to be in an Adverse Cytogenetic Risk Group - Event is defined as death or transformation to AML in participants with MDS or CMML, which ever occurs first. Transformation to AML is 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 is defined as death in participants with low-blast AML.
Timepoint [26] 0 0
From randomization until transformation to AML if eligible or death : up to 6 years
Secondary outcome [27] 0 0
Overall Survival in Participants who have TP53 Mutations, 17p Deletions, and/or are Determined to be in an Adverse Cytogenetic Risk Group - OS is calculated from date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis will be censored as of the date the participant was last known to be alive.
Timepoint [27] 0 0
From randomization until death : up to 6 years
Secondary outcome [28] 0 0
Percentage of Participants with Overall Response by Cycle 6 - 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=complete remission(CR)and partial remission(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.
Timepoint [28] 0 0
Up to Cycle 6 (up to approximately Day 168)

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).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,TAS
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Icon Cancer Care Wesley - Auchenflower
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Icon Cancer Care Chermside - Chermside
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Icon Cancer Care South Brisbane - South Brisbane
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Icon Cancer Care - South Brisbane
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Icon Cancer Care Southport - Southport
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Royal Hobart Hospital - Hobart
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Liverpool Hospital - Liverpool
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4066 - Auchenflower
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4032 - Chermside
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4101 - South Brisbane
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4215 - Southport
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7000 - Hobart
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1871 - Liverpool
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Swansea

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Millennium Pharmaceuticals, Inc.
Address
Country

Ethics approval
Ethics application status

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).
Trial website
https://clinicaltrials.gov/show/NCT03268954
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director Clinical Science
Address 0 0
Millennium Pharmaceuticals, Inc.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications