An Efficacy and Safety Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML) and Low-Blast Acute Myelogenous Leukemia (AML)

Sponsor
Millennium Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02610777
Collaborator
(none)
120
Enrollment
59
Locations
2
Arms
62.9
Actual Duration (Months)
2
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of pevonedistat plus azacitidine versus single-agent azacitidine in participants with HR-MDS or CMML, or low-blast AML.

Detailed Description

The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to treat people with MDS or CMML, or low-blast 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 120 participants. Once enrolled, participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in 28-day treatment cycles:

  • Pevonedistat 20 mg/m2 and azacitidine 75 mg/m2 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 worldwide. The overall time to participate in this study is approximately 44 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 will enter event-free survival follow-up or response follow-up (study visits every 3 months) if their disease has not transformed to AML (for participants with HR MDS or CMML) or progressed (for participants with low-blast AML), and they have not started subsequent therapy. Participants will also enter overall survival follow-up (contacted every 3 months to document subsequent therapies and survival status).

Study Design

Study Type:
Interventional
Actual Enrollment :
120 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Low-Blast Acute Myelogenous Leukemia
Actual Study Start Date :
Apr 14, 2016
Actual Primary Completion Date :
Sep 4, 2019
Actual Study Completion Date :
Jul 12, 2021

Arms and Interventions

ArmIntervention/Treatment
Active Comparator: Azacitidine

Azacitidine 75 milligram per square meter (mg/m^2), intravenously or subcutaneously, on Days 1 to 5, Days 8 and 9 in 28-day treatment cycles.

Drug: Azacitidine
Azacitidine intravenous or subcutaneous formulation.

Experimental: Azacitidine + Pevonedistat

Azacitidine 75 mg/m^2, intravenously or subcutaneously, on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m^2, 60-minute (+ or - 10) infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles.

Drug: Azacitidine
Azacitidine intravenous or subcutaneous formulation.

Drug: Pevonedistat
Pevonedistat intravenous infusion.

Outcome Measures

Primary Outcome Measures

  1. Overall Survival (OS) [From date of randomization until death (up to 3 years and 5 months)]

    OS was defined as the time from the date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis were censored at the date the participant was last known to be alive.

Secondary Outcome Measures

  1. Event-Free Survival (EFS) [From date of randomization until transformation to AML, or death due to any cause (up to 5 years and 9 months)]

    EFS is defined as the time from the date of randomization to the date of the occurrence of an event. An event is defined as death or transformation to AML for HR MDS/CMML participants, whichever occurs first, or defined as death for low-blast AML participants. HR MDS/CMML participants without documented EFS event will be censored at the date of the last response assessment. HR MDS/CMML participants with no response assessment and no death will be censored at the date of randomization. Low-blast AML participants without documentation of death will be censored at the date the participant was last known to be alive. HR MDS/CMML participants who received alternative antineoplastic therapy before death or transformation to AML will be censored at the date of last adequate assessment prior to starting alternate antineoplastic therapy. Data for this outcome measure will be reported after study completion (which is planned for 2022).

  2. Six-month Survival Rate [Month 6]

    Six-month survival rate (at 6 months) was defined as the Kaplan-Meier estimate of survival rate at 6 months. OS was defined as the time from the date of randomization to the date of death due to any cause. Data for this outcome measure will be reported after study completion (which is planned for 2022).

  3. One-year Survival Rate [Month 12]

    One-year survival rate (at 12 months) was defined as the Kaplan-Meier estimate of survival rate at 12 months. OS was defined as the time from the date of randomization to the date of death due to any cause. Data for this outcome measure will be reported after study completion (which is planned for 2022).

  4. Time to AML Transformation in HR MDS or CMML Participants [From date of randomization until transformation to AML (up to 5 years and 9 months)]

    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 World Health Organization (WHO) classification, as a participant having >20% blasts in the blood or marrow and increase of blast count by 50%. Data for this outcome measure will be reported after study completion (which is planned for 2022).

  5. Percentage of Participants With Complete Remission (CR) [From date of randomization until CR (up to 5 years and 9 months)]

    Disease responses for HR MDS or CMML is based on the modified International Working Group (IWG) response criteria for MDS and for low-blast AML on the revised IWG response criteria for AML. CR for HR MDS or CMML: 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 gram/deciliter (g/dL) hemoglobin (Hb), >=100*10^9/liter (/L) platelets (plt), >=1.0*10^9/L absolute neutrophil count (ANC) and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP) (<100*10^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).

  6. Percentage of Participants With CR and Partial Remission (PR) [From date of randomization until CR and PR (up to 5 years and 9 months)]

    Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow ,>=11 g/dL Hb;>=100*10^9/L plt; >=1.0*10^9/L ANC and 0% blasts in peripheral blood. PR for HR MDS/CMML:considered achieved if all CR criteria is met except for bone marrow blasts decreased by >=50%over pretreatment but still >5%. CR for low-blast AML: morphologic leukemia-free state, ANC of >1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML:fulfill all criteria for CR except for residual neutropenia (<100*10^9/L)/TTP(<100*10^9/L). PR for low-blast AML:all hematological values for CR but with decrease of >=50% in percentage of blasts to 5%-25% in bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).

  7. Percentage of Participants With Overall Response [From date of randomization until CR, PR, or hematologic improvement (HI) (up to 5 years and 9 months)]

    Disease responses (HR MDS/CMML): modified IWG criteria for MDS; low-blast (LB) AML: revised IWG criteria for AML. Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with incomplete blood count recovery(Cri)+PR.HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of bone marrow (BM) cell lines,>=11g/dL Hb,>=100*10^9/L plt,>=1.0*10^9/L ANC,0% blasts in peripheral blood; PR:CR criteria met except BM blasts>=50%less over pretreatment but still>5%; HI:hb increase (inc)>=1.5g/dL if baseline<11g/dL;plt inc>=30*10^9/L if baseline>20*10^9/L/Inc. from <20*10^9/L->20*10^9/L, ANC inc. by 100%;absolute inc. of>0.5*10^9/L if baseline<100*10^9/L. LB AML-CR:morphologic leukemia-freestate>1.0*10^9ANC,>=100*10^9/L plt, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR hematological values but>=50%less in BM aspirate. Data will be reported after study completion (which is planned for 2022).

  8. Percentage of Participants With CR in Low-blast AML [From date of randomization until CR (up to 5 years and 9 months)]

    Disease response for low-blast AML is based on the revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP) (<100*10^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).

  9. Percentage of Participants With CR by Cycle 4 [From date of randomization until CR by Cycle 4 (cycle length is equal to [=] 28 days)]

    Disease responses for HR MDS or CMML were based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=100*10^9/L plt, ANC >=1.0*10^9/L and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L).Data for this outcome measure will be reported after study completion (which is planned for 2022).

  10. Percentage of Participants With CR and PR by Cycle 4 [From date of randomization until CR and PR, by Cycle 4 (cycle length=28 days)]

    Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, >=11 g/dL Hb; >=100*10^9/L plt; >=1.0*10^9/L ANC and 0% blasts in peripheral blood.PR for HR MDS/CMML: considered achieved if all CR criteria is met except for bone marrow blasts decreased by>=50% over pretreatment but still>5%.CR for low-blast AML: morphologic leukemia-free state, ANC of>1.0*10^9/L and plt of>=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: fulfill all criteria for CR except for residual neutropenia (<100*10^9/L)/TTP (<100*10^9/L). PR for low-blast AML: all hematological values for CR but with decrease of >=50% in percentage of blasts to 5%-25% in bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).

  11. Percentage of Participants With Overall Response by Cycle 4 [From date of randomization until CR, PR or HI, by Cycle 4 (cycle length=28 days)]

    Disease responses (HR MDS/CMML): modified IWG criteria for MDS; low-blast (LB) AML: revised IWG criteria for AML. Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with incomplete blood count recovery(Cri)+PR.HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of bone marrow (BM) cell lines,>=11g/dL Hb,>=100*10^9/L plt,>=1.0*10^9/L ANC,0% blasts in peripheral blood; PR:CR criteria met except BM blasts>=50%less over pretreatment but still>5%; HI:hb increase (inc)>=1.5g/dL if baseline<11g/dL;plt inc>=30*10^9/L if baseline>20*10^9/L/Inc. from <20*10^9/L->20*10^9/L, ANC inc. by 100%;absolute inc. of>0.5*10^9/L if baseline<100*10^9/L. LB AML-CR:morphologic leukemia-freestate>1.0*10^9ANC,>=100*10^9/L plt, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR hematological values but>=50%less in BM aspirate. Data will be reported after study completion (which is planned for 2022).

  12. Percentage of Participants With CR in Low-blast AML by Cycle 4 [From the date of randomization until CR by Cycle 4 (cycle length=28 days)]

    Disease response for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and ptl of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).

  13. Duration of CR [From date of randomization until CR (up to 5 years and 9 months)]

    Duration of CR will be analyzed using standard survival analysis techniques based on Kaplan Meier estimates. Disease responses for HR MDS or CMML are based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=100*10^9/L plt, >=1.0*10^9/L ANC and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).

  14. Duration of CR and PR [From date of randomization until CR or PR (up to 5 years and 9 months)]

    Duration of CR and PR will be analyzed by standard survival analysis techniques based on Kaplan Meier estimates. Disease responses (HR MDS/CMML) are based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. For HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hb, >=100*10^9/L plt,>=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%; low-blast AML-CR: morphologic leukemia-free state, >1.0*10^9/L ANC ,plt >=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/TTP <100*10^9/L;PR:all CR hematological values but with a decrease of >=50% in blasts percentage to 5%-25% in bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).

  15. Duration of Overall Response [From date of randomization until CR, PR or HI (up to 5 years and 9 months)]

    Disease responses(HR MDS/CMML): modified IWG criteria for MDS;low-blast(LB)AML: revised IWG criteria for AML.Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+CR with incomplete blood count recovery(Cri)+PR.HR MDS/CMML-CR: <=5%myeloblasts with normal maturation of bone marrow (BM) cell lines, >=11g/dL Hb,>=100*10^9/L plt, >=1.0*10^9/L ANC,0%blasts in peripheral blood; PR:CR criteria met except BM blasts >=50%less over pretreatment but still>5%; HI:hb increase(inc) >=1.5g/dL if baseline<11g/dL; plt inc>=30*10^9/L if baseline >20*10^9/L inc from<20*10^9/L->20*10^9/L,ANC inc by100%; absolute inc of >0.5*10^9/L if baseline <100*10^9/L.LB AML-CR: morphologic leukemia-freestate >1.0*10^9 ANC, >=100*1 ^9/Lplt, transfusion independence, no residual evidence of extramedullary leukemia; CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L; PR:all CR hematological values but>=50%less in BM aspirate. Data will be reported after study completion (which is planned for 2022).

  16. Duration of CR in Low-blast AML [From date of randomization until CR (up to 5 years and 9 months)]

    Duration of CR was analyzed using standard survival analysis techniques based on Kaplan Meier estimates. Disease responses for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).

  17. Time to First CR or PR [From date of randomization until CR or PR (up to 5 years and 9 months)]

    Time to first CR or PR: time from randomization to first documented CR or PR, whichever occurs first. Disease responses (HR MDS/CMML) based on modified IWG response criteria for MDS; low-blast AML on revised IWG response criteria for AML. HR MDS/CMML-CR: <=5% myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hb, >=100*10^9/L plt,>=1.0*10^9/L ANC, 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 ANC, plt >=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/TTP <100*10^9/L; PR: all CR hematological values but with a decrease of >=50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).

  18. Time to Subsequent Therapy [From date of randomization up to 5 year 9 months]

    Time to subsequent therapy is defined as time from randomization to the date of the first subsequent therapy. Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity. Participants who discontinue study treatment to receive single-agent azacitidine off study will not be counted as receiving subsequent therapy. Data for this outcome measure will be reported after study completion (which is planned for 2022).

  19. Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence [8 weeks before randomization through 30 days after last dose of any study drug (up to 5 years and 9 months)]

    A participant was 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 randomization 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. Data for this outcome measure will be reported after study completion (which is planned for 2022).

  20. Percentage of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML [From date of randomization until transformation to AML or until initiation of subsequent therapy (up to 5 years and 9 months)]

    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%. Data for this outcome measure will be reported after study completion (which is planned for 2022).

  21. Time to Progressive Disease (PD), Relapse, or Death [From date of randomization until PD, relapse or death (up to 5 years and 9 months)]

    Time from randomization until PD/transformation to AML/relapse/death due to any cause, whichever occurs first. Relapse after CR or PR in MDS/CMML: return to pretreatment bone marrow blast % or decrement of >=50% from maximum remission levels in ANC or plt, reduction in Hb concentration by >=1.5 g/dL or transfusion dependence. PD: at least 50% decrement from maximum remission in ANC or plt, or reduction in Hb by>=2g/dL or transfusion dependence;participants with <5% blasts: >=50% increase (inc) in blasts to >5%; 5%-10%: >=50% inc to >10%; 10%-20%: >=50% inc to>20%;20%-30%:>=50% inc to >30%. Relapse after CR in Low blast AML: reappearance of leukemic blasts in peripheral blood or >=5% blasts in bone marrow not attributable to any cause (example, bone marrow regeneration after consolidation therapy). If there are no circulating blasts, bone marrow contains 5%-20% blasts, a repeat analysis is performed a week later. Data will be reported after study completion (which is planned for 2022).

  22. Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [From date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)]

    Data for this outcome measure will be reported after study completion (which is planned for 2022).

  23. Number of Participants With Markedly Abnormal Clinical Laboratory Values [From date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)]

    Data for this outcome measure will be reported after study completion (which is planned for 2022).

  24. Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status [From date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)]

    Number of participants with change from Baseline in ECOG performance status was measured on 6 point scale to assess participant's performance status, where: Grade 0(Normal activity. Fully active, able to carry on all pre-disease activities without restriction); Grade 1(Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); Grade 2(In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours); Grade 3(In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours); Grade 4(100% bedridden. Completely disabled, cannot carry on any self-care, totally confined to bed or chair); Grade 5(Dead). Data for this outcome measure will be reported after study completion (which is planned for 2022).

  25. Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG) Values [From date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)]

    Data for this outcome measure will be reported after study completion (which is planned for 2022).

  26. Number of Participants With Clinically Significant Change From Baseline Values in Vital Signs [From date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)]

    Data for this outcome measure will be reported after study completion (which is planned for 2022).

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  1. Male or female participants 18 years or older.

  2. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with white blood cells [WBC] <20,000 per microliter [/mcL]) or low blast AML based on 1 of the following:

French American British (FAB) Classifications:
  • Refractory anemia with excess blasts (RAEB) - defined as having 5% to 20% myeloblasts in the bone marrow.

  • CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.

OR

WHO Classifications:
  • RAEB 1 - defined as having 5% to 9% myeloblasts in the bone marrow.

  • RAEB 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.

  • CMML 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.

  • CMML 1 (Although CMML 1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these participants may enroll only if bone marrow blasts >=5%.

  • WHO defined AML with 20% to 30% myeloblasts in the bone marrow and <30% myeloblasts in peripheral blood who are deemed by the investigator to be appropriate for azacitidine based therapy.

  1. For MDS and CMML participants, prognostic risk category, based on the Revised
International Prognostic Scoring System (IPSS R), of:
  • Very high (>6 points),

  • High (>4.5 to 6 points), or

  • Intermediate (>3 to 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.

  1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

  2. Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug):

  • Albumin >2.7 g/dL.

  • Total bilirubin <upper limit of normal (ULN) except in participants with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct bilirubin <=1.5*ULN of the direct bilirubin.

  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5*ULN.

  • Creatinine clearance >=50 milliliter per minutes (mL/min).

  • Hb >8 g/dL. Participants may be transfused to achieve this value. Elevated indirect bilirubin due to post transfusion hemolysis is allowed.

  1. For CMML participants: WBC count <20,000/mcL before administration of the first dose of study drug on Cycle 1 Day 1; participants must have been off hydroxyurea for at least 1 week prior to WBC count assessment.

  2. Ability to undergo the study required bone marrow sample collection procedures.

  3. Suitable venous access for the study required blood sampling (that is, including pharmacokinetic (PK) and biomarker sampling).

  4. Female participants who:

  • Are postmenopausal for at least 1 year before the Screening visit , or

  • Are surgically sterile, or

  • If they are of childbearing potential, agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, or

  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).

Male participants, even if surgically sterilized (that is, status postvasectomy), who:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or

  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).

  1. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
Exclusion Criteria:
  1. Previous treatment with decitabine or azacitidine or other hypomethylating agent.

  2. 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. Eligible for allogenic stem cell transplantation.

  4. Participants with MDS, CMML, or low blast AML, whose only site of disease is extramedullary, example, the skin.

  5. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures or could limit participant expected survival to less than 6 months.

  6. Treatment with any anti leukemic/anti MDS therapies (example, lenalidomide, cytarabine, anthracyclines, purine analogs) or with any investigational products within 14 days before the first dose of any study drug.

  7. Known hypersensitivity to mannitol.

  8. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.

  9. Major surgery within 14 days before first dose or a scheduled surgery during study period; insertion of a venous access device (example, catheter, port) is not considered major surgery.

  10. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.

  11. Life threatening illness unrelated to cancer.

  12. Prothrombin time (PT) or prolongation of the activated thromboplastin time (aPTT) >1.5 ULN or active uncontrolled coagulopathy or bleeding disorder.

  13. Known human immunodeficiency virus (HIV) seropositive.

  14. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Participants who have isolated positive hepatitis B core antibody (that is, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.

  15. Known hepatic cirrhosis or severe pre-existing hepatic impairment.

  16. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III or

  1. and/or myocardial infarction within 6 months prior to first dose, or severe pulmonary hypertension. As an example, well controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.
  1. Treatment with strong cytochrome P450 (CYP) 3A inhibitors or inducers within 14 days before the first dose of study drug.

  2. Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 12 months before the first dose of any study drug, except for hydroxyurea.

  3. Female participants who are lactating and breast feeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.

  4. Female participants who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).

  5. Male participants who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1University of AlabamaBirminghamAlabamaUnited States35233
2Greenville Health SystemLittle RockArkansasUnited States72201
3UC San Diego Moores Cancer CenterLa JollaCaliforniaUnited States92093-098
4Compassionate Cancer Care Medical Group IncorporatedRiversideCaliforniaUnited States92501
5Rocky Mountain Cancer CentersAuroraColoradoUnited States80012
6Smilow Cancer Center at Yale New Haven HospitalNew HavenConnecticutUnited States6510
7University of Miami Miller School of MedicineMiamiFloridaUnited States33136
8H Lee Moffitt Cancer Center and Research InstituteTampaFloridaUnited States33612
9University of Chicago Medical CenterChicagoIllinoisUnited States60637
10Johns Hopkins UniversityBaltimoreMarylandUnited States21287
11San Juan Oncology AssociatesFarmingtonNew MexicoUnited States87401
12Monter Cancer CenterLake SuccessNew YorkUnited States11042
13Weill Cornell Medical CollegeNew YorkNew YorkUnited States10021
14Columbia University Medical CenterNew YorkNew YorkUnited States10032
15University of Rochester Medical CenterRochesterNew YorkUnited States14603
16University of North Carolina at Chapel HillChapel HillNorth CarolinaUnited States27599
17Cleveland ClinicClevelandOhioUnited States44195
18Cancer Care Center of South TexasNew BraunfelsTexasUnited States78130
19Nebraska Cancer SpecialistsThe WoodlandsTexasUnited States77380
20Texas Oncology - Waco, TXTylerTexasUnited States76712
21University of VirginiaCharlottesvilleVirginiaUnited States22903
22Medical Oncology AssociatesSpokaneWashingtonUnited States99208
23Yakima Valley Memorial HospitalYakimaWashingtonUnited States98902
24AZ Sint-Jan AVBruggeWest-VlaanderenBelgium8400
25Grand Hopital de Charleroi asblCharleroiBelgium6000
26Cliniques Universitaires UCL de Mont-GodinneYvoirBelgium5500
27University Multiprofile Hospital for Active Treatment Sv Ivan Rilski EADSofiaBulgaria1113
28Specialized Hospital for Active Treatment of Haematological Diseases - SofiaSofiaBulgaria1756
29University Multi-Profile Hospital for Active Treatment Dr Georgi StranskiSofiaBulgaria1756
30Sunnybrook Health Science CentreTorontoOntarioCanadaM4N 3M5
31Princess Margaret HospitalTorontoOntarioCanadaM5G 2M9
32Fakultni Nemocnice BrnoBrnoCzechia625 00
33Fakultni Nemocnice Kralovske VinohradyPraha 10Czechia10034
34CHU de GRENOBLEGrenobleFrance38700
35CHRU LilleLilleFrance59000
36Hopital Saint LouisParisFrance75010
37Marien Hospital Akademisches LehrkrankenhausDusseldorfGermany40479
38Universitatsklinikum UlmUlmGermany89081
39Tallaght HospitalDublinIreland24
40University Hospital GalwayGalwayIreland
41Shaare Zedek Medical CenterJerusalemIsrael9103102
42ZIV Medical CenterSafedIsrael13100
43Tel Aviv Sourasky Medical CenterTel AvivIsrael13100
44Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola MalpighiBolognaItaly40138
45Azienda Ospedaliera Universitaria CareggiFirenzeItaly50139
46Azienda Ospedaliera Bianchi Melacrino MorelliReggio CalabriaItaly89100
47Azienda Ospedaliero Universitaria San Giovanni Battista Di TorinoTorinoItaly10126
48Zuyderland Medisch CentrumSittardNetherlands6162 BG
49Hospital Universitario Son EspasesPalma de MallorcaBalearesSpain7010
50Hospital Universitario Quironsalud MadridPozuelo De AlarconMadridSpain28223
51Hospital Universitario Germans Trias i PujolBadalonaSpain8916
52ICO I'Hospitalet Hospital Duran i Reynals Instituto Catalan de Oncologia de Hospitalet (ICO)BarcelonaSpain08908
53Hospital Clinic de BarcelonaBarcelonaSpain8036
54Hospital General Universitario Gregorio MaranonMadridSpain28007
55Hospital Universitario La PazMadridSpain28046
56Hospital Regional Universitario de Malaga - Hospital Universitario Virgen de la VictoriaMalagaSpain29010
57Hospital Universitario de SalamancaSalamancaSpain37007
58Hospital Clinico Universitario de ValenciaValenciaSpain46010
59Hospital Universitari i Politecnic La Fe de ValenciaValenciaSpain46026

Sponsors and Collaborators

  • Millennium Pharmaceuticals, Inc.

Investigators

  • Study Director: Medical Director Clinical Science, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02610777
Other Study ID Numbers:
  • Pevonedistat-2001
  • U1111-1169-6540
  • 2015-000221-37
  • REec-2016-2145
  • Pevonedistat-2001CTID
First Posted:
Nov 20, 2015
Last Update Posted:
Aug 12, 2021
Last Verified:
Aug 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Millennium Pharmaceuticals, Inc.
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment DetailsParticipants took part in the study at 59 investigative sites in the United States, Canada, Belgium, Bulgaria, Czech Republic, Germany, Spain, France, Ireland, Israel, and Italy. Results are reported based on the primary completion date of 04 September 2019.
Pre-assignment DetailParticipants with higher-risk myelodysplastic syndrome (HR MDS) or chronic myelomonocytic leukemia (CMML) or low-blast acute myelogenous leukemia (AML) were enrolled in this study to receive one of the two treatments: single-agent azacitidine or the combination of pevonedistat and azacitidine.
Arm/Group TitleAzacitidine 75 mg/m^2Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
Arm/Group DescriptionAzacitidine 75 milligram per square meter (mg/m^2), infusion, intravenously or subcutaneously, on Days 1 to 5, and on Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Days 1 to 5, and on Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).
Period Title: Overall Study
STARTED6258
COMPLETED4136
NOT COMPLETED2122

Baseline Characteristics

Arm/Group TitleAzacitidine 75 mg/m^2Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2Total
Arm/Group DescriptionAzacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Days 1 to 5, and on Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Days 1 to 5, and on Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).Total of all reporting groups
Overall Participants6258120
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
69.5
(8.87)
71.7
(9.63)
70.6
(9.27)
Sex: Female, Male (Count of Participants)
Female
21
33.9%
16
27.6%
37
30.8%
Male
41
66.1%
42
72.4%
83
69.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
3
4.8%
4
6.9%
7
5.8%
Not Hispanic or Latino
55
88.7%
52
89.7%
107
89.2%
Unknown or Not Reported
4
6.5%
2
3.4%
6
5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
3
4.8%
1
1.7%
4
3.3%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
3
4.8%
2
3.4%
5
4.2%
White
54
87.1%
52
89.7%
106
88.3%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
2
3.2%
3
5.2%
5
4.2%
Region of Enrollment (Count of Participants)
Canada
3
4.8%
3
5.2%
6
5%
United States
27
43.5%
18
31%
45
37.5%
Belgium
5
8.1%
5
8.6%
10
8.3%
Bulgaria
5
8.1%
10
17.2%
15
12.5%
Czech Republic
3
4.8%
1
1.7%
4
3.3%
Germany
0
0%
1
1.7%
1
0.8%
Spain
8
12.9%
14
24.1%
22
18.3%
France
1
1.6%
1
1.7%
2
1.7%
Ireland
1
1.6%
0
0%
1
0.8%
Israel
3
4.8%
0
0%
3
2.5%
Italy
6
9.7%
5
8.6%
11
9.2%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]
169.12
(10.857)
168.87
(7.510)
169.00
(9.352)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]
79.19
(18.471)
75.95
(13.716)
77.62
(16.359)
Body Surface Area (square meter (m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [square meter (m^2)]
1.92
(0.265)
1.88
(0.201)
1.90
(0.236)

Outcome Measures

1. Primary Outcome
TitleOverall Survival (OS)
DescriptionOS was defined as the time from the date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis were censored at the date the participant was last known to be alive.
Time FrameFrom date of randomization until death (up to 3 years and 5 months)

Outcome Measure Data

Analysis Population Description
The ITT population was defined as all participants who were randomized.
Arm/Group TitleAzacitidine 75 mg/m^2Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
Arm/Group DescriptionAzacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Days 1 to 5, and on Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Days 1 to 5, and on Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).
Measure Participants6258
Median (95% Confidence Interval) [months]
19.0
21.8
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Azacitidine 75 mg/m^2, Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
Comments Hazard Ratio (HR) was based on an unstratified Cox proportional hazard regression model with treatment as a factor. P-value is from an unstratified log-rank test.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value0.334
Comments
MethodLog Rank
Comments
Method of EstimationEstimation ParameterHazard Ratio (HR)
Estimated Value0.802
Confidence Interval (2-Sided) 95%
0.512 to 1.256
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
TitleEvent-Free Survival (EFS)
DescriptionEFS is defined as the time from the date of randomization to the date of the occurrence of an event. An event is defined as death or transformation to AML for HR MDS/CMML participants, whichever occurs first, or defined as death for low-blast AML participants. HR MDS/CMML participants without documented EFS event will be censored at the date of the last response assessment. HR MDS/CMML participants with no response assessment and no death will be censored at the date of randomization. Low-blast AML participants without documentation of death will be censored at the date the participant was last known to be alive. HR MDS/CMML participants who received alternative antineoplastic therapy before death or transformation to AML will be censored at the date of last adequate assessment prior to starting alternate antineoplastic therapy. Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until transformation to AML, or death due to any cause (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
3. Secondary Outcome
TitleSix-month Survival Rate
DescriptionSix-month survival rate (at 6 months) was defined as the Kaplan-Meier estimate of survival rate at 6 months. OS was defined as the time from the date of randomization to the date of death due to any cause. Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameMonth 6

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
4. Secondary Outcome
TitleOne-year Survival Rate
DescriptionOne-year survival rate (at 12 months) was defined as the Kaplan-Meier estimate of survival rate at 12 months. OS was defined as the time from the date of randomization to the date of death due to any cause. Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameMonth 12

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
5. Secondary Outcome
TitleTime to AML Transformation in HR MDS or CMML Participants
DescriptionTime 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 World Health Organization (WHO) classification, as a participant having >20% blasts in the blood or marrow and increase of blast count by 50%. Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until transformation to AML (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
6. Secondary Outcome
TitlePercentage of Participants With Complete Remission (CR)
DescriptionDisease responses for HR MDS or CMML is based on the modified International Working Group (IWG) response criteria for MDS and for low-blast AML on the revised IWG response criteria for AML. CR for HR MDS or CMML: 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 gram/deciliter (g/dL) hemoglobin (Hb), >=100*10^9/liter (/L) platelets (plt), >=1.0*10^9/L absolute neutrophil count (ANC) and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP) (<100*10^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
7. Secondary Outcome
TitlePercentage of Participants With CR and Partial Remission (PR)
DescriptionDisease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow ,>=11 g/dL Hb;>=100*10^9/L plt; >=1.0*10^9/L ANC and 0% blasts in peripheral blood. PR for HR MDS/CMML:considered achieved if all CR criteria is met except for bone marrow blasts decreased by >=50%over pretreatment but still >5%. CR for low-blast AML: morphologic leukemia-free state, ANC of >1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML:fulfill all criteria for CR except for residual neutropenia (<100*10^9/L)/TTP(<100*10^9/L). PR for low-blast AML:all hematological values for CR but with decrease of >=50% in percentage of blasts to 5%-25% in bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR and PR (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
8. Secondary Outcome
TitlePercentage of Participants With Overall Response
DescriptionDisease responses (HR MDS/CMML): modified IWG criteria for MDS; low-blast (LB) AML: revised IWG criteria for AML. Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with incomplete blood count recovery(Cri)+PR.HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of bone marrow (BM) cell lines,>=11g/dL Hb,>=100*10^9/L plt,>=1.0*10^9/L ANC,0% blasts in peripheral blood; PR:CR criteria met except BM blasts>=50%less over pretreatment but still>5%; HI:hb increase (inc)>=1.5g/dL if baseline<11g/dL;plt inc>=30*10^9/L if baseline>20*10^9/L/Inc. from <20*10^9/L->20*10^9/L, ANC inc. by 100%;absolute inc. of>0.5*10^9/L if baseline<100*10^9/L. LB AML-CR:morphologic leukemia-freestate>1.0*10^9ANC,>=100*10^9/L plt, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR hematological values but>=50%less in BM aspirate. Data will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR, PR, or hematologic improvement (HI) (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
9. Secondary Outcome
TitlePercentage of Participants With CR in Low-blast AML
DescriptionDisease response for low-blast AML is based on the revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP) (<100*10^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
10. Secondary Outcome
TitlePercentage of Participants With CR by Cycle 4
DescriptionDisease responses for HR MDS or CMML were based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=100*10^9/L plt, ANC >=1.0*10^9/L and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L).Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR by Cycle 4 (cycle length is equal to [=] 28 days)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
11. Secondary Outcome
TitlePercentage of Participants With CR and PR by Cycle 4
DescriptionDisease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, >=11 g/dL Hb; >=100*10^9/L plt; >=1.0*10^9/L ANC and 0% blasts in peripheral blood.PR for HR MDS/CMML: considered achieved if all CR criteria is met except for bone marrow blasts decreased by>=50% over pretreatment but still>5%.CR for low-blast AML: morphologic leukemia-free state, ANC of>1.0*10^9/L and plt of>=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: fulfill all criteria for CR except for residual neutropenia (<100*10^9/L)/TTP (<100*10^9/L). PR for low-blast AML: all hematological values for CR but with decrease of >=50% in percentage of blasts to 5%-25% in bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR and PR, by Cycle 4 (cycle length=28 days)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
12. Secondary Outcome
TitlePercentage of Participants With Overall Response by Cycle 4
DescriptionDisease responses (HR MDS/CMML): modified IWG criteria for MDS; low-blast (LB) AML: revised IWG criteria for AML. Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with incomplete blood count recovery(Cri)+PR.HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of bone marrow (BM) cell lines,>=11g/dL Hb,>=100*10^9/L plt,>=1.0*10^9/L ANC,0% blasts in peripheral blood; PR:CR criteria met except BM blasts>=50%less over pretreatment but still>5%; HI:hb increase (inc)>=1.5g/dL if baseline<11g/dL;plt inc>=30*10^9/L if baseline>20*10^9/L/Inc. from <20*10^9/L->20*10^9/L, ANC inc. by 100%;absolute inc. of>0.5*10^9/L if baseline<100*10^9/L. LB AML-CR:morphologic leukemia-freestate>1.0*10^9ANC,>=100*10^9/L plt, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR hematological values but>=50%less in BM aspirate. Data will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR, PR or HI, by Cycle 4 (cycle length=28 days)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
13. Secondary Outcome
TitlePercentage of Participants With CR in Low-blast AML by Cycle 4
DescriptionDisease response for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and ptl of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom the date of randomization until CR by Cycle 4 (cycle length=28 days)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
14. Secondary Outcome
TitleDuration of CR
DescriptionDuration of CR will be analyzed using standard survival analysis techniques based on Kaplan Meier estimates. Disease responses for HR MDS or CMML are based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=100*10^9/L plt, >=1.0*10^9/L ANC and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
15. Secondary Outcome
TitleDuration of CR and PR
DescriptionDuration of CR and PR will be analyzed by standard survival analysis techniques based on Kaplan Meier estimates. Disease responses (HR MDS/CMML) are based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. For HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hb, >=100*10^9/L plt,>=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%; low-blast AML-CR: morphologic leukemia-free state, >1.0*10^9/L ANC ,plt >=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/TTP <100*10^9/L;PR:all CR hematological values but with a decrease of >=50% in blasts percentage to 5%-25% in bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR or PR (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
16. Secondary Outcome
TitleDuration of Overall Response
DescriptionDisease responses(HR MDS/CMML): modified IWG criteria for MDS;low-blast(LB)AML: revised IWG criteria for AML.Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+CR with incomplete blood count recovery(Cri)+PR.HR MDS/CMML-CR: <=5%myeloblasts with normal maturation of bone marrow (BM) cell lines, >=11g/dL Hb,>=100*10^9/L plt, >=1.0*10^9/L ANC,0%blasts in peripheral blood; PR:CR criteria met except BM blasts >=50%less over pretreatment but still>5%; HI:hb increase(inc) >=1.5g/dL if baseline<11g/dL; plt inc>=30*10^9/L if baseline >20*10^9/L inc from<20*10^9/L->20*10^9/L,ANC inc by100%; absolute inc of >0.5*10^9/L if baseline <100*10^9/L.LB AML-CR: morphologic leukemia-freestate >1.0*10^9 ANC, >=100*1 ^9/Lplt, transfusion independence, no residual evidence of extramedullary leukemia; CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L; PR:all CR hematological values but>=50%less in BM aspirate. Data will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR, PR or HI (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
17. Secondary Outcome
TitleDuration of CR in Low-blast AML
DescriptionDuration of CR was analyzed using standard survival analysis techniques based on Kaplan Meier estimates. Disease responses for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
18. Secondary Outcome
TitleTime to First CR or PR
DescriptionTime to first CR or PR: time from randomization to first documented CR or PR, whichever occurs first. Disease responses (HR MDS/CMML) based on modified IWG response criteria for MDS; low-blast AML on revised IWG response criteria for AML. HR MDS/CMML-CR: <=5% myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hb, >=100*10^9/L plt,>=1.0*10^9/L ANC, 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 ANC, plt >=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/TTP <100*10^9/L; PR: all CR hematological values but with a decrease of >=50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until CR or PR (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
19. Secondary Outcome
TitleTime to Subsequent Therapy
DescriptionTime to subsequent therapy is defined as time from randomization to the date of the first subsequent therapy. Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity. Participants who discontinue study treatment to receive single-agent azacitidine off study will not be counted as receiving subsequent therapy. Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization up to 5 year 9 months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
20. Secondary Outcome
TitlePercentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence
DescriptionA participant was 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 randomization 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. Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time Frame8 weeks before randomization through 30 days after last dose of any study drug (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
21. Secondary Outcome
TitlePercentage of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML
DescriptionInpatient 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%. Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until transformation to AML or until initiation of subsequent therapy (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
22. Secondary Outcome
TitleTime to Progressive Disease (PD), Relapse, or Death
DescriptionTime from randomization until PD/transformation to AML/relapse/death due to any cause, whichever occurs first. Relapse after CR or PR in MDS/CMML: return to pretreatment bone marrow blast % or decrement of >=50% from maximum remission levels in ANC or plt, reduction in Hb concentration by >=1.5 g/dL or transfusion dependence. PD: at least 50% decrement from maximum remission in ANC or plt, or reduction in Hb by>=2g/dL or transfusion dependence;participants with <5% blasts: >=50% increase (inc) in blasts to >5%; 5%-10%: >=50% inc to >10%; 10%-20%: >=50% inc to>20%;20%-30%:>=50% inc to >30%. Relapse after CR in Low blast AML: reappearance of leukemic blasts in peripheral blood or >=5% blasts in bone marrow not attributable to any cause (example, bone marrow regeneration after consolidation therapy). If there are no circulating blasts, bone marrow contains 5%-20% blasts, a repeat analysis is performed a week later. Data will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization until PD, relapse or death (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
23. Secondary Outcome
TitleNumber of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
DescriptionData for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
24. Secondary Outcome
TitleNumber of Participants With Markedly Abnormal Clinical Laboratory Values
DescriptionData for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
25. Secondary Outcome
TitleNumber of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status
DescriptionNumber of participants with change from Baseline in ECOG performance status was measured on 6 point scale to assess participant's performance status, where: Grade 0(Normal activity. Fully active, able to carry on all pre-disease activities without restriction); Grade 1(Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); Grade 2(In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours); Grade 3(In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours); Grade 4(100% bedridden. Completely disabled, cannot carry on any self-care, totally confined to bed or chair); Grade 5(Dead). Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
26. Secondary Outcome
TitleNumber of Participants With Significant Change From Baseline in Electrocardiogram (ECG) Values
DescriptionData for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
27. Secondary Outcome
TitleNumber of Participants With Clinically Significant Change From Baseline Values in Vital Signs
DescriptionData for this outcome measure will be reported after study completion (which is planned for 2022).
Time FrameFrom date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description

Adverse Events

Time FrameTEAEs are adverse events (AEs) that started after the date of randomization up to 30 days after administration of the last dose of any study drug (up to 3 years and 5 months)
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group TitleAzacitidine 75 mg/m^2Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
Arm/Group DescriptionAzacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Days 1 to 5, and on Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Days 1 to 5, and on Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).
All Cause Mortality
Azacitidine 75 mg/m^2Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total41/62 (66.1%) 36/58 (62.1%)
Serious Adverse Events
Azacitidine 75 mg/m^2Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total39/62 (62.9%) 40/58 (69%)
Blood and lymphatic system disorders
Febrile neutropenia13/62 (21%) 1513/58 (22.4%) 20
Anaemia2/62 (3.2%) 20/58 (0%) 0
Thrombocytopenia1/62 (1.6%) 11/58 (1.7%) 1
Autoimmune haemolytic anaemia1/62 (1.6%) 10/58 (0%) 0
Leukopenia1/62 (1.6%) 10/58 (0%) 0
Neutropenia1/62 (1.6%) 10/58 (0%) 0
Cardiac disorders
Atrial fibrillation1/62 (1.6%) 11/58 (1.7%) 1
Angina unstable0/62 (0%) 01/58 (1.7%) 1
Atrial flutter0/62 (0%) 01/58 (1.7%) 1
Atrioventricular block0/62 (0%) 01/58 (1.7%) 1
Atrioventricular block second degree0/62 (0%) 01/58 (1.7%) 1
Cardiac failure0/62 (0%) 01/58 (1.7%) 1
Cardiac failure acute0/62 (0%) 01/58 (1.7%) 1
Cardio-respiratory arrest0/62 (0%) 01/58 (1.7%) 1
Congestive cardiomyopathy1/62 (1.6%) 10/58 (0%) 0
Left ventricular failure0/62 (0%) 01/58 (1.7%) 1
Myocardial infarction1/62 (1.6%) 10/58 (0%) 0
Supraventricular tachycardia1/62 (1.6%) 10/58 (0%) 0
Ear and labyrinth disorders
Ear pain0/62 (0%) 01/58 (1.7%) 1
Eye disorders
Parophthalmia0/62 (0%) 01/58 (1.7%) 1
Gastrointestinal disorders
Abdominal pain0/62 (0%) 02/58 (3.4%) 2
Diarrhoea0/62 (0%) 02/58 (3.4%) 2
Constipation1/62 (1.6%) 10/58 (0%) 0
Gastric haemorrhage1/62 (1.6%) 10/58 (0%) 0
Gastritis erosive1/62 (1.6%) 10/58 (0%) 0
Gastrointestinal necrosis1/62 (1.6%) 10/58 (0%) 0
Gastrointestinal ulcer perforation1/62 (1.6%) 10/58 (0%) 0
Inguinal hernia1/62 (1.6%) 10/58 (0%) 0
Ischaemic gastritis1/62 (1.6%) 10/58 (0%) 0
Melaena0/62 (0%) 01/58 (1.7%) 1
Proctitis0/62 (0%) 01/58 (1.7%) 1
Rectal haemorrhage1/62 (1.6%) 10/58 (0%) 0
General disorders
Pyrexia6/62 (9.7%) 83/58 (5.2%) 3
Multiple organ dysfunction syndrome1/62 (1.6%) 11/58 (1.7%) 1
Asthenia0/62 (0%) 01/58 (1.7%) 1
Malaise1/62 (1.6%) 20/58 (0%) 0
Non-cardiac chest pain0/62 (0%) 01/58 (1.7%) 1
Death1/62 (1.6%) 10/58 (0%) 0
Hepatobiliary disorders
Hepatic lesion1/62 (1.6%) 10/58 (0%) 0
Immune system disorders
Drug hypersensitivity1/62 (1.6%) 10/58 (0%) 0
Infections and infestations
Pneumonia5/62 (8.1%) 77/58 (12.1%) 11
Sepsis4/62 (6.5%) 43/58 (5.2%) 3
Cellulitis2/62 (3.2%) 22/58 (3.4%) 2
Bacteraemia1/62 (1.6%) 12/58 (3.4%) 2
Endocarditis1/62 (1.6%) 12/58 (3.4%) 2
Bronchopulmonary aspergillosis1/62 (1.6%) 11/58 (1.7%) 1
Influenza1/62 (1.6%) 11/58 (1.7%) 1
Lung infection1/62 (1.6%) 31/58 (1.7%) 1
Upper respiratory tract infection0/62 (0%) 02/58 (3.4%) 2
Wound infection1/62 (1.6%) 11/58 (1.7%) 1
Abscess limb0/62 (0%) 01/58 (1.7%) 1
Arthritis bacterial0/62 (0%) 01/58 (1.7%) 1
Arthritis infective0/62 (0%) 01/58 (1.7%) 1
Bacterial sepsis1/62 (1.6%) 10/58 (0%) 0
Bronchitis0/62 (0%) 01/58 (1.7%) 1
Corona virus infection0/62 (0%) 01/58 (1.7%) 1
Localised infection0/62 (0%) 01/58 (1.7%) 1
Lower respiratory tract infection1/62 (1.6%) 10/58 (0%) 0
Oral viral infection0/62 (0%) 01/58 (1.7%) 1
Pseudomonas infection0/62 (0%) 01/58 (1.7%) 1
Pulmonary sepsis0/62 (0%) 01/58 (1.7%) 1
Respiratory syncytial virus bronchiolitis0/62 (0%) 01/58 (1.7%) 1
Respiratory tract infection1/62 (1.6%) 10/58 (0%) 0
Sinusitis0/62 (0%) 01/58 (1.7%) 1
Soft tissue infection1/62 (1.6%) 10/58 (0%) 0
Staphylococcal bacteraemia0/62 (0%) 01/58 (1.7%) 1
Urinary tract infection1/62 (1.6%) 10/58 (0%) 0
Urinary tract infection enterococcal1/62 (1.6%) 10/58 (0%) 0
Viral infection0/62 (0%) 01/58 (1.7%) 1
Injury, poisoning and procedural complications
Ankle fracture1/62 (1.6%) 10/58 (0%) 0
Fall1/62 (1.6%) 10/58 (0%) 0
Hip fracture0/62 (0%) 01/58 (1.7%) 1
Postoperative hypotension1/62 (1.6%) 10/58 (0%) 0
Spinal compression fracture1/62 (1.6%) 10/58 (0%) 0
Metabolism and nutrition disorders
Failure to thrive1/62 (1.6%) 10/58 (0%) 0
Hyperglycaemia0/62 (0%) 01/58 (1.7%) 1
Musculoskeletal and connective tissue disorders
Back pain0/62 (0%) 02/58 (3.4%) 2
Arthritis1/62 (1.6%) 20/58 (0%) 0
Arthritis reactive1/62 (1.6%) 10/58 (0%) 0
Chondrocalcinosis pyrophosphate0/62 (0%) 01/58 (1.7%) 1
Osteonecrosis0/62 (0%) 01/58 (1.7%) 1
Rotator cuff syndrome0/62 (0%) 01/58 (1.7%) 1
Pain in jaw0/62 (0%) 01/58 (1.7%) 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia1/62 (1.6%) 10/58 (0%) 0
Myelodysplastic syndrome1/62 (1.6%) 10/58 (0%) 0
Myelodysplastic syndrome transformation1/62 (1.6%) 10/58 (0%) 0
Squamous cell carcinoma of skin0/62 (0%) 01/58 (1.7%) 2
Nervous system disorders
Cerebrovascular accident2/62 (3.2%) 30/58 (0%) 0
Cauda equina syndrome1/62 (1.6%) 10/58 (0%) 0
Cerebral ischaemia0/62 (0%) 01/58 (1.7%) 1
Embolic stroke1/62 (1.6%) 10/58 (0%) 0
Haemorrhage intracranial1/62 (1.6%) 10/58 (0%) 0
Headache1/62 (1.6%) 10/58 (0%) 0
Psychiatric disorders
Mental status changes0/62 (0%) 02/58 (3.4%) 2
Renal and urinary disorders
Acute kidney injury0/62 (0%) 02/58 (3.4%) 2
Urinary tract obstruction1/62 (1.6%) 11/58 (1.7%) 1
Anuria0/62 (0%) 01/58 (1.7%) 1
Chronic kidney disease1/62 (1.6%) 10/58 (0%) 0
Haematuria0/62 (0%) 01/58 (1.7%) 1
Renal colic1/62 (1.6%) 10/58 (0%) 0
Renal failure0/62 (0%) 01/58 (1.7%) 1
Reproductive system and breast disorders
Benign prostatic hyperplasia0/62 (0%) 01/58 (1.7%) 1
Respiratory, thoracic and mediastinal disorders
Dyspnoea1/62 (1.6%) 11/58 (1.7%) 1
Hypoxia1/62 (1.6%) 20/58 (0%) 0
Lung infiltration1/62 (1.6%) 10/58 (0%) 0
Pulmonary embolism0/62 (0%) 01/58 (1.7%) 2
Respiratory distress0/62 (0%) 01/58 (1.7%) 1
Respiratory failure0/62 (0%) 01/58 (1.7%) 1
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis1/62 (1.6%) 10/58 (0%) 0
Vascular disorders
Deep vein thrombosis0/62 (0%) 01/58 (1.7%) 1
Haematoma0/62 (0%) 01/58 (1.7%) 1
Peripheral venous disease0/62 (0%) 01/58 (1.7%) 1
Thrombophlebitis superficial1/62 (1.6%) 10/58 (0%) 0
Other (Not Including Serious) Adverse Events
Azacitidine 75 mg/m^2Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total60/62 (96.8%) 52/58 (89.7%)
Blood and lymphatic system disorders
Anaemia26/62 (41.9%) 4818/58 (31%) 35
Neutropenia18/62 (29%) 3920/58 (34.5%) 62
Thrombocytopenia14/62 (22.6%) 3413/58 (22.4%) 35
Febrile neutropenia5/62 (8.1%) 72/58 (3.4%) 2
Cardiac disorders
Tachycardia2/62 (3.2%) 24/58 (6.9%) 4
Ear and labyrinth disorders
Ear pain0/62 (0%) 03/58 (5.2%) 3
Eye disorders
Conjunctival haemorrhage2/62 (3.2%) 33/58 (5.2%) 3
Gastrointestinal disorders
Constipation29/62 (46.8%) 3821/58 (36.2%) 38
Nausea28/62 (45.2%) 3920/58 (34.5%) 34
Diarrhoea17/62 (27.4%) 2818/58 (31%) 25
Vomiting13/62 (21%) 1714/58 (24.1%) 22
Abdominal pain10/62 (16.1%) 113/58 (5.2%) 5
Haemorrhoids2/62 (3.2%) 25/58 (8.6%) 6
Stomatitis5/62 (8.1%) 51/58 (1.7%) 1
General disorders
Pyrexia22/62 (35.5%) 3121/58 (36.2%) 36
Fatigue25/62 (40.3%) 3312/58 (20.7%) 20
Asthenia12/62 (19.4%) 1917/58 (29.3%) 27
Oedema peripheral8/62 (12.9%) 1112/58 (20.7%) 17
Chills7/62 (11.3%) 74/58 (6.9%) 4
Injection site pain7/62 (11.3%) 74/58 (6.9%) 5
Peripheral swelling2/62 (3.2%) 25/58 (8.6%) 6
Non-cardiac chest pain Pain4/62 (6.5%) 62/58 (3.4%) 2
Malaise4/62 (6.5%) 40/58 (0%) 0
Injection site reaction0/62 (0%) 03/58 (5.2%) 3
Pain3/62 (4.8%) 33/58 (5.2%) 3
Infections and infestations
Nasopharyngitis4/62 (6.5%) 47/58 (12.1%) 10
Pneumonia6/62 (9.7%) 63/58 (5.2%) 3
Urinary tract infection4/62 (6.5%) 105/58 (8.6%) 8
Oral candidiasis4/62 (6.5%) 43/58 (5.2%) 3
Oral herpes6/62 (9.7%) 71/58 (1.7%) 1
Bronchitis6/62 (9.7%) 60/58 (0%) 0
Respiratory tract infection3/62 (4.8%) 33/58 (5.2%) 3
Injury, poisoning and procedural complications
Fall6/62 (9.7%) 67/58 (12.1%) 9
Contusion4/62 (6.5%) 45/58 (8.6%) 5
Investigations
Neutrophil count decreased6/62 (9.7%) 1812/58 (20.7%) 22
Platelet count decreased7/62 (11.3%) 197/58 (12.1%) 10
Weight decreased5/62 (8.1%) 55/58 (8.6%) 7
White blood cell count decreased6/62 (9.7%) 114/58 (6.9%) 12
Aspartate aminotransferase increased5/62 (8.1%) 84/58 (6.9%) 6
Alanine aminotransferase increased4/62 (6.5%) 84/58 (6.9%) 7
Blood bilirubin increased3/62 (4.8%) 53/58 (5.2%) 8
Blood creatinine increased3/62 (4.8%) 53/58 (5.2%) 3
Blood alkaline phosphatase increased2/62 (3.2%) 93/58 (5.2%) 4
Metabolism and nutrition disorders
Decreased appetite12/62 (19.4%) 1611/58 (19%) 11
Hypokalaemia11/62 (17.7%) 174/58 (6.9%) 5
Hyponatraemia4/62 (6.5%) 84/58 (6.9%) 16
Hypocalcaemia4/62 (6.5%) 53/58 (5.2%) 5
Hypomagnesaemia4/62 (6.5%) 63/58 (5.2%) 3
Dehydration4/62 (6.5%) 52/58 (3.4%) 3
Hyperkalaemia3/62 (4.8%) 93/58 (5.2%) 3
Hypoalbuminaemia4/62 (6.5%) 102/58 (3.4%) 4
Hypophosphataemia4/62 (6.5%) 41/58 (1.7%) 1
Musculoskeletal and connective tissue disorders
Arthralgia12/62 (19.4%) 155/58 (8.6%) 6
Back pain8/62 (12.9%) 99/58 (15.5%) 11
Pain in extremity4/62 (6.5%) 510/58 (17.2%) 12
Muscular weakness5/62 (8.1%) 62/58 (3.4%) 3
Muscle spasms3/62 (4.8%) 53/58 (5.2%) 3
Musculoskeletal pain4/62 (6.5%) 41/58 (1.7%) 1
Myalgia2/62 (3.2%) 23/58 (5.2%) 3
Nervous system disorders
Dizziness8/62 (12.9%) 108/58 (13.8%) 11
Headache8/62 (12.9%) 103/58 (5.2%) 4
Somnolence1/62 (1.6%) 13/58 (5.2%) 3
Psychiatric disorders
Insomnia7/62 (11.3%) 86/58 (10.3%) 6
Depression2/62 (3.2%) 24/58 (6.9%) 5
Renal and urinary disorders
Dysuria2/62 (3.2%) 34/58 (6.9%) 4
Haematuria1/62 (1.6%) 23/58 (5.2%) 4
Acute kidney injury0/62 (0%) 03/58 (5.2%) 3
Respiratory, thoracic and mediastinal disorders
Cough21/62 (33.9%) 2522/58 (37.9%) 31
Dyspnoea15/62 (24.2%) 1913/58 (22.4%) 15
Epistaxis6/62 (9.7%) 613/58 (22.4%) 27
Productive cough4/62 (6.5%) 56/58 (10.3%) 7
Nasal congestion4/62 (6.5%) 55/58 (8.6%) 5
Oropharyngeal pain6/62 (9.7%) 63/58 (5.2%) 3
Pleural effusion5/62 (8.1%) 52/58 (3.4%) 2
Dyspnoea exertional2/62 (3.2%) 23/58 (5.2%) 3
Skin and subcutaneous tissue disorders
Erythema5/62 (8.1%) 64/58 (6.9%) 5
Pruritus6/62 (9.7%) 61/58 (1.7%) 1
Petechiae4/62 (6.5%) 41/58 (1.7%) 1
Vascular disorders
Haematoma2/62 (3.2%) 27/58 (12.1%) 11
Hypotension3/62 (4.8%) 46/58 (10.3%) 7
Hypertension2/62 (3.2%) 24/58 (6.9%) 4
Pallor1/62 (1.6%) 13/58 (5.2%) 3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.

Results Point of Contact

Name/TitleMedical Director
OrganizationTakeda
Phone+1-877-825-3327
Emailtrialdisclosures@takeda.com
Responsible Party:
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02610777
Other Study ID Numbers:
  • Pevonedistat-2001
  • U1111-1169-6540
  • 2015-000221-37
  • REec-2016-2145
  • Pevonedistat-2001CTID
First Posted:
Nov 20, 2015
Last Update Posted:
Aug 12, 2021
Last Verified:
Aug 1, 2021