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)
• Enrollment: 120
• Locations: 59
• Arms: 2
• Actual Duration (Months): 63.3
• Patients Per Site: 2
• Patients Per Site Per Month: 0

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukemia, Myeloid, Acute	Drug: Azacitidine; Drug: Pevonedistat	Phase 2

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/m^{2 and azacitidine 75 mg/m}2 combination

• Single-agent azacitidine 75 mg/m^2

All participants will receive azacitidine via intravenous or subcutaneous route. Participants randomized to the combination arm will also receive pevonedistat intravenous infusion.

This multi-center trial will be conducted 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 23, 2021

Arms and Interventions

Arm	Intervention/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

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35233
2	Greenville Health System	Little Rock	Arkansas	United States	72201
3	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093
4	Compassionate Cancer Care Medical Group Incorporated	Riverside	California	United States	92501
5	Rocky Mountain Cancer Centers	Aurora	Colorado	United States	80012
6	Smilow Cancer Center at Yale New Haven Hospital	New Haven	Connecticut	United States	06510
7	University of Miami Miller School of Medicine	Miami	Florida	United States	33136
8	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
9	University of Chicago Medical Center	Chicago	Illinois	United States	60637
10	Johns Hopkins University	Baltimore	Maryland	United States	21287
11	San Juan Oncology Associates	Farmington	New Mexico	United States	87401
12	Monter Cancer Center	Lake Success	New York	United States	11042
13	Weill Cornell Medical College	New York	New York	United States	10021
14	Columbia University Medical Center	New York	New York	United States	10032
15	University of Rochester Medical Center	Rochester	New York	United States	14603
16	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
17	Cleveland Clinic	Cleveland	Ohio	United States	44195
18	Cancer Care Center of South Texas	New Braunfels	Texas	United States	78130
19	Nebraska Cancer Specialists	The Woodlands	Texas	United States	77380
20	Texas Oncology - Waco, TX	Tyler	Texas	United States	76712
21	University of Virginia	Charlottesville	Virginia	United States	22903
22	Medical Oncology Associates	Spokane	Washington	United States	99208
23	Yakima Valley Memorial Hospital	Yakima	Washington	United States	98902
24	AZ Sint-Jan AV	Brugge	West-Vlaanderen	Belgium	8400
25	Grand Hopital de Charleroi asbl	Charleroi		Belgium	6000
26	Cliniques Universitaires UCL de Mont-Godinne	Yvoir		Belgium	5500
27	University Multiprofile Hospital for Active Treatment Sv Ivan Rilski EAD	Sofia		Bulgaria	1113
28	Specialized Hospital for Active Treatment of Haematological Diseases - Sofia	Sofia		Bulgaria	1756
29	University Multi-Profile Hospital for Active Treatment Dr Georgi Stranski	Sofia		Bulgaria	1756
30	Sunnybrook Health Science Centre	Toronto	Ontario	Canada	M4N 3M5
31	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
32	Fakultni Nemocnice Brno	Brno		Czechia	625 00
33	Fakultni Nemocnice Kralovske Vinohrady	Praha 10		Czechia	10034
34	CHU de GRENOBLE	Grenoble		France	38700
35	CHRU Lille	Lille		France	59000
36	Hopital Saint Louis	Paris		France	75010
37	Marien Hospital Akademisches Lehrkrankenhaus	Dusseldorf		Germany	40479
38	Universitatsklinikum Ulm	Ulm		Germany	89081
39	Tallaght Hospital	Dublin		Ireland	24
40	University Hospital Galway	Galway		Ireland
41	Shaare Zedek Medical Center	Jerusalem		Israel	9103102
42	ZIV Medical Center	Safed		Israel	13100
43	Tel Aviv Sourasky Medical Center	Tel Aviv		Israel	13100
44	Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi	Bologna		Italy	40138
45	Azienda Ospedaliera Universitaria Careggi	Firenze		Italy	50139
46	Azienda Ospedaliera Bianchi Melacrino Morelli	Reggio Calabria		Italy	89100
47	Azienda Ospedaliero Universitaria San Giovanni Battista Di Torino	Torino		Italy	10126
48	Zuyderland Medisch Centrum	Sittard		Netherlands	6162 BG
49	Hospital Universitario Son Espases	Palma de Mallorca	Baleares	Spain	7010
50	Hospital Universitario Quironsalud Madrid	Pozuelo De Alarcon	Madrid	Spain	28223
51	Hospital Universitario Germans Trias i Pujol	Badalona		Spain	8916
52	ICO I'Hospitalet Hospital Duran i Reynals Instituto Catalan de Oncologia de Hospitalet (ICO)	Barcelona		Spain	08908
53	Hospital Clinic de Barcelona	Barcelona		Spain	8036
54	Hospital General Universitario Gregorio Maranon	Madrid		Spain	28007
55	Hospital Universitario La Paz	Madrid		Spain	28046
56	Hospital Regional Universitario de Malaga - Hospital Universitario Virgen de la Victoria	Malaga		Spain	29010
57	Hospital Universitario de Salamanca	Salamanca		Spain	37007
58	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
59	Hospital Universitari i Politecnic La Fe de Valencia	Valencia		Spain	46026

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Jul 27, 2018
• Statistical Analysis Plan - Aug 6, 2019

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: Jun 7, 2022
• Last Verified: May 1, 2022

• 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.: Drug Therapy
• Additional relevant MeSH terms: Leukemia; Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Syndrome; Azacitidine; Pevonedistat

Study Results

Participant Flow

Recruitment Details	Participants 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 Detail	Participants 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 Title	Azacitidine 75 mg/m^2	Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
Arm/Group Description	Azacitidine 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
STARTED	62	58
COMPLETED	41	36
NOT COMPLETED	21	22

Baseline Characteristics

Arm/Group Title	Azacitidine 75 mg/m^2	Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2	Total
Arm/Group Description	Azacitidine 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 Participants	62	58	120
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

Title	Overall Survival (OS)
Description	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.
Time Frame	From 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 Title	Azacitidine 75 mg/m^2	Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
Arm/Group Description	Azacitidine 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 Participants	62	58
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 Hypothesis	p-Value	0.334
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.802
	Confidence Interval	(2-Sided) 95%; 0.512 to 1.256
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Event-Free Survival (EFS)
Description	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).
Time Frame	From 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

Title	Six-month Survival Rate
Description	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).
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	One-year Survival Rate
Description	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).
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Time to AML Transformation in HR MDS or CMML Participants
Description	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).
Time Frame	From 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

Title	Percentage of Participants With Complete Remission (CR)
Description	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).
Time Frame	From 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

Title	Percentage of Participants With CR and Partial Remission (PR)
Description	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).
Time Frame	From 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

Title	Percentage of Participants With Overall Response
Description	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).
Time Frame	From 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

Title	Percentage of Participants With CR in Low-blast AML
Description	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).
Time Frame	From 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

Title	Percentage of Participants With CR by Cycle 4
Description	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).
Time Frame	From 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

Title	Percentage of Participants With CR and PR by Cycle 4
Description	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).
Time Frame	From 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

Title	Percentage of Participants With Overall Response by Cycle 4
Description	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).
Time Frame	From 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

Title	Percentage of Participants With CR in Low-blast AML by Cycle 4
Description	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).
Time Frame	From 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

Title	Duration of CR
Description	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).
Time Frame	From 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

Title	Duration of CR and PR
Description	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).
Time Frame	From 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

Title	Duration of Overall Response
Description	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).
Time Frame	From 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

Title	Duration of CR in Low-blast AML
Description	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).
Time Frame	From 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

Title	Time to First CR or PR
Description	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).
Time Frame	From 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

Title	Time to Subsequent Therapy
Description	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).
Time Frame	From 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

Title	Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence
Description	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).
Time Frame	8 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

Title	Percentage of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML
Description	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).
Time Frame	From 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

Title	Time to Progressive Disease (PD), Relapse, or Death
Description	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).
Time Frame	From 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

Title	Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description	Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time Frame	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

24. Secondary Outcome

Title	Number of Participants With Markedly Abnormal Clinical Laboratory Values
Description	Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time Frame	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

25. Secondary Outcome

Title	Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status
Description	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).
Time Frame	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

26. Secondary Outcome

Title	Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG) Values
Description	Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time Frame	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

27. Secondary Outcome

Title	Number of Participants With Clinically Significant Change From Baseline Values in Vital Signs
Description	Data for this outcome measure will be reported after study completion (which is planned for 2022).
Time Frame	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	TEAEs 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 Title	Azacitidine 75 mg/m^2		Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
Arm/Group Description	Azacitidine 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^2		Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/62 (66.1%)		36/58 (62.1%)
Serious Adverse Events
	Azacitidine 75 mg/m^2		Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/62 (62.9%)		40/58 (69%)
Blood and lymphatic system disorders
Febrile neutropenia	13/62 (21%)	15	13/58 (22.4%)	20
Anaemia	2/62 (3.2%)	2	0/58 (0%)	0
Thrombocytopenia	1/62 (1.6%)	1	1/58 (1.7%)	1
Autoimmune haemolytic anaemia	1/62 (1.6%)	1	0/58 (0%)	0
Leukopenia	1/62 (1.6%)	1	0/58 (0%)	0
Neutropenia	1/62 (1.6%)	1	0/58 (0%)	0
Cardiac disorders
Atrial fibrillation	1/62 (1.6%)	1	1/58 (1.7%)	1
Angina unstable	0/62 (0%)	0	1/58 (1.7%)	1
Atrial flutter	0/62 (0%)	0	1/58 (1.7%)	1
Atrioventricular block	0/62 (0%)	0	1/58 (1.7%)	1
Atrioventricular block second degree	0/62 (0%)	0	1/58 (1.7%)	1
Cardiac failure	0/62 (0%)	0	1/58 (1.7%)	1
Cardiac failure acute	0/62 (0%)	0	1/58 (1.7%)	1
Cardio-respiratory arrest	0/62 (0%)	0	1/58 (1.7%)	1
Congestive cardiomyopathy	1/62 (1.6%)	1	0/58 (0%)	0
Left ventricular failure	0/62 (0%)	0	1/58 (1.7%)	1
Myocardial infarction	1/62 (1.6%)	1	0/58 (0%)	0
Supraventricular tachycardia	1/62 (1.6%)	1	0/58 (0%)	0
Ear and labyrinth disorders
Ear pain	0/62 (0%)	0	1/58 (1.7%)	1
Eye disorders
Parophthalmia	0/62 (0%)	0	1/58 (1.7%)	1
Gastrointestinal disorders
Abdominal pain	0/62 (0%)	0	2/58 (3.4%)	2
Diarrhoea	0/62 (0%)	0	2/58 (3.4%)	2
Constipation	1/62 (1.6%)	1	0/58 (0%)	0
Gastric haemorrhage	1/62 (1.6%)	1	0/58 (0%)	0
Gastritis erosive	1/62 (1.6%)	1	0/58 (0%)	0
Gastrointestinal necrosis	1/62 (1.6%)	1	0/58 (0%)	0
Gastrointestinal ulcer perforation	1/62 (1.6%)	1	0/58 (0%)	0
Inguinal hernia	1/62 (1.6%)	1	0/58 (0%)	0
Ischaemic gastritis	1/62 (1.6%)	1	0/58 (0%)	0
Melaena	0/62 (0%)	0	1/58 (1.7%)	1
Proctitis	0/62 (0%)	0	1/58 (1.7%)	1
Rectal haemorrhage	1/62 (1.6%)	1	0/58 (0%)	0
General disorders
Pyrexia	6/62 (9.7%)	8	3/58 (5.2%)	3
Multiple organ dysfunction syndrome	1/62 (1.6%)	1	1/58 (1.7%)	1
Asthenia	0/62 (0%)	0	1/58 (1.7%)	1
Malaise	1/62 (1.6%)	2	0/58 (0%)	0
Non-cardiac chest pain	0/62 (0%)	0	1/58 (1.7%)	1
Death	1/62 (1.6%)	1	0/58 (0%)	0
Hepatobiliary disorders
Hepatic lesion	1/62 (1.6%)	1	0/58 (0%)	0
Immune system disorders
Drug hypersensitivity	1/62 (1.6%)	1	0/58 (0%)	0
Infections and infestations
Pneumonia	5/62 (8.1%)	7	7/58 (12.1%)	11
Sepsis	4/62 (6.5%)	4	3/58 (5.2%)	3
Cellulitis	2/62 (3.2%)	2	2/58 (3.4%)	2
Bacteraemia	1/62 (1.6%)	1	2/58 (3.4%)	2
Endocarditis	1/62 (1.6%)	1	2/58 (3.4%)	2
Bronchopulmonary aspergillosis	1/62 (1.6%)	1	1/58 (1.7%)	1
Influenza	1/62 (1.6%)	1	1/58 (1.7%)	1
Lung infection	1/62 (1.6%)	3	1/58 (1.7%)	1
Upper respiratory tract infection	0/62 (0%)	0	2/58 (3.4%)	2
Wound infection	1/62 (1.6%)	1	1/58 (1.7%)	1
Abscess limb	0/62 (0%)	0	1/58 (1.7%)	1
Arthritis bacterial	0/62 (0%)	0	1/58 (1.7%)	1
Arthritis infective	0/62 (0%)	0	1/58 (1.7%)	1
Bacterial sepsis	1/62 (1.6%)	1	0/58 (0%)	0
Bronchitis	0/62 (0%)	0	1/58 (1.7%)	1
Corona virus infection	0/62 (0%)	0	1/58 (1.7%)	1
Localised infection	0/62 (0%)	0	1/58 (1.7%)	1
Lower respiratory tract infection	1/62 (1.6%)	1	0/58 (0%)	0
Oral viral infection	0/62 (0%)	0	1/58 (1.7%)	1
Pseudomonas infection	0/62 (0%)	0	1/58 (1.7%)	1
Pulmonary sepsis	0/62 (0%)	0	1/58 (1.7%)	1
Respiratory syncytial virus bronchiolitis	0/62 (0%)	0	1/58 (1.7%)	1
Respiratory tract infection	1/62 (1.6%)	1	0/58 (0%)	0
Sinusitis	0/62 (0%)	0	1/58 (1.7%)	1
Soft tissue infection	1/62 (1.6%)	1	0/58 (0%)	0
Staphylococcal bacteraemia	0/62 (0%)	0	1/58 (1.7%)	1
Urinary tract infection	1/62 (1.6%)	1	0/58 (0%)	0
Urinary tract infection enterococcal	1/62 (1.6%)	1	0/58 (0%)	0
Viral infection	0/62 (0%)	0	1/58 (1.7%)	1
Injury, poisoning and procedural complications
Ankle fracture	1/62 (1.6%)	1	0/58 (0%)	0
Fall	1/62 (1.6%)	1	0/58 (0%)	0
Hip fracture	0/62 (0%)	0	1/58 (1.7%)	1
Postoperative hypotension	1/62 (1.6%)	1	0/58 (0%)	0
Spinal compression fracture	1/62 (1.6%)	1	0/58 (0%)	0
Metabolism and nutrition disorders
Failure to thrive	1/62 (1.6%)	1	0/58 (0%)	0
Hyperglycaemia	0/62 (0%)	0	1/58 (1.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/62 (0%)	0	2/58 (3.4%)	2
Arthritis	1/62 (1.6%)	2	0/58 (0%)	0
Arthritis reactive	1/62 (1.6%)	1	0/58 (0%)	0
Chondrocalcinosis pyrophosphate	0/62 (0%)	0	1/58 (1.7%)	1
Osteonecrosis	0/62 (0%)	0	1/58 (1.7%)	1
Rotator cuff syndrome	0/62 (0%)	0	1/58 (1.7%)	1
Pain in jaw	0/62 (0%)	0	1/58 (1.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/62 (1.6%)	1	0/58 (0%)	0
Myelodysplastic syndrome	1/62 (1.6%)	1	0/58 (0%)	0
Myelodysplastic syndrome transformation	1/62 (1.6%)	1	0/58 (0%)	0
Squamous cell carcinoma of skin	0/62 (0%)	0	1/58 (1.7%)	2
Nervous system disorders
Cerebrovascular accident	2/62 (3.2%)	3	0/58 (0%)	0
Cauda equina syndrome	1/62 (1.6%)	1	0/58 (0%)	0
Cerebral ischaemia	0/62 (0%)	0	1/58 (1.7%)	1
Embolic stroke	1/62 (1.6%)	1	0/58 (0%)	0
Haemorrhage intracranial	1/62 (1.6%)	1	0/58 (0%)	0
Headache	1/62 (1.6%)	1	0/58 (0%)	0
Psychiatric disorders
Mental status changes	0/62 (0%)	0	2/58 (3.4%)	2
Renal and urinary disorders
Acute kidney injury	0/62 (0%)	0	2/58 (3.4%)	2
Urinary tract obstruction	1/62 (1.6%)	1	1/58 (1.7%)	1
Anuria	0/62 (0%)	0	1/58 (1.7%)	1
Chronic kidney disease	1/62 (1.6%)	1	0/58 (0%)	0
Haematuria	0/62 (0%)	0	1/58 (1.7%)	1
Renal colic	1/62 (1.6%)	1	0/58 (0%)	0
Renal failure	0/62 (0%)	0	1/58 (1.7%)	1
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/62 (0%)	0	1/58 (1.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/62 (1.6%)	1	1/58 (1.7%)	1
Hypoxia	1/62 (1.6%)	2	0/58 (0%)	0
Lung infiltration	1/62 (1.6%)	1	0/58 (0%)	0
Pulmonary embolism	0/62 (0%)	0	1/58 (1.7%)	2
Respiratory distress	0/62 (0%)	0	1/58 (1.7%)	1
Respiratory failure	0/62 (0%)	0	1/58 (1.7%)	1
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis	1/62 (1.6%)	1	0/58 (0%)	0
Vascular disorders
Deep vein thrombosis	0/62 (0%)	0	1/58 (1.7%)	1
Haematoma	0/62 (0%)	0	1/58 (1.7%)	1
Peripheral venous disease	0/62 (0%)	0	1/58 (1.7%)	1
Thrombophlebitis superficial	1/62 (1.6%)	1	0/58 (0%)	0
Other (Not Including Serious) Adverse Events
	Azacitidine 75 mg/m^2		Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/62 (96.8%)		52/58 (89.7%)
Blood and lymphatic system disorders
Anaemia	26/62 (41.9%)	48	18/58 (31%)	35
Neutropenia	18/62 (29%)	39	20/58 (34.5%)	62
Thrombocytopenia	14/62 (22.6%)	34	13/58 (22.4%)	35
Febrile neutropenia	5/62 (8.1%)	7	2/58 (3.4%)	2
Cardiac disorders
Tachycardia	2/62 (3.2%)	2	4/58 (6.9%)	4
Ear and labyrinth disorders
Ear pain	0/62 (0%)	0	3/58 (5.2%)	3
Eye disorders
Conjunctival haemorrhage	2/62 (3.2%)	3	3/58 (5.2%)	3
Gastrointestinal disorders
Constipation	29/62 (46.8%)	38	21/58 (36.2%)	38
Nausea	28/62 (45.2%)	39	20/58 (34.5%)	34
Diarrhoea	17/62 (27.4%)	28	18/58 (31%)	25
Vomiting	13/62 (21%)	17	14/58 (24.1%)	22
Abdominal pain	10/62 (16.1%)	11	3/58 (5.2%)	5
Haemorrhoids	2/62 (3.2%)	2	5/58 (8.6%)	6
Stomatitis	5/62 (8.1%)	5	1/58 (1.7%)	1
General disorders
Pyrexia	22/62 (35.5%)	31	21/58 (36.2%)	36
Fatigue	25/62 (40.3%)	33	12/58 (20.7%)	20
Asthenia	12/62 (19.4%)	19	17/58 (29.3%)	27
Oedema peripheral	8/62 (12.9%)	11	12/58 (20.7%)	17
Chills	7/62 (11.3%)	7	4/58 (6.9%)	4
Injection site pain	7/62 (11.3%)	7	4/58 (6.9%)	5
Peripheral swelling	2/62 (3.2%)	2	5/58 (8.6%)	6
Non-cardiac chest pain Pain	4/62 (6.5%)	6	2/58 (3.4%)	2
Malaise	4/62 (6.5%)	4	0/58 (0%)	0
Injection site reaction	0/62 (0%)	0	3/58 (5.2%)	3
Pain	3/62 (4.8%)	3	3/58 (5.2%)	3
Infections and infestations
Nasopharyngitis	4/62 (6.5%)	4	7/58 (12.1%)	10
Pneumonia	6/62 (9.7%)	6	3/58 (5.2%)	3
Urinary tract infection	4/62 (6.5%)	10	5/58 (8.6%)	8
Oral candidiasis	4/62 (6.5%)	4	3/58 (5.2%)	3
Oral herpes	6/62 (9.7%)	7	1/58 (1.7%)	1
Bronchitis	6/62 (9.7%)	6	0/58 (0%)	0
Respiratory tract infection	3/62 (4.8%)	3	3/58 (5.2%)	3
Injury, poisoning and procedural complications
Fall	6/62 (9.7%)	6	7/58 (12.1%)	9
Contusion	4/62 (6.5%)	4	5/58 (8.6%)	5
Investigations
Neutrophil count decreased	6/62 (9.7%)	18	12/58 (20.7%)	22
Platelet count decreased	7/62 (11.3%)	19	7/58 (12.1%)	10
Weight decreased	5/62 (8.1%)	5	5/58 (8.6%)	7
White blood cell count decreased	6/62 (9.7%)	11	4/58 (6.9%)	12
Aspartate aminotransferase increased	5/62 (8.1%)	8	4/58 (6.9%)	6
Alanine aminotransferase increased	4/62 (6.5%)	8	4/58 (6.9%)	7
Blood bilirubin increased	3/62 (4.8%)	5	3/58 (5.2%)	8
Blood creatinine increased	3/62 (4.8%)	5	3/58 (5.2%)	3
Blood alkaline phosphatase increased	2/62 (3.2%)	9	3/58 (5.2%)	4
Metabolism and nutrition disorders
Decreased appetite	12/62 (19.4%)	16	11/58 (19%)	11
Hypokalaemia	11/62 (17.7%)	17	4/58 (6.9%)	5
Hyponatraemia	4/62 (6.5%)	8	4/58 (6.9%)	16
Hypocalcaemia	4/62 (6.5%)	5	3/58 (5.2%)	5
Hypomagnesaemia	4/62 (6.5%)	6	3/58 (5.2%)	3
Dehydration	4/62 (6.5%)	5	2/58 (3.4%)	3
Hyperkalaemia	3/62 (4.8%)	9	3/58 (5.2%)	3
Hypoalbuminaemia	4/62 (6.5%)	10	2/58 (3.4%)	4
Hypophosphataemia	4/62 (6.5%)	4	1/58 (1.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	12/62 (19.4%)	15	5/58 (8.6%)	6
Back pain	8/62 (12.9%)	9	9/58 (15.5%)	11
Pain in extremity	4/62 (6.5%)	5	10/58 (17.2%)	12
Muscular weakness	5/62 (8.1%)	6	2/58 (3.4%)	3
Muscle spasms	3/62 (4.8%)	5	3/58 (5.2%)	3
Musculoskeletal pain	4/62 (6.5%)	4	1/58 (1.7%)	1
Myalgia	2/62 (3.2%)	2	3/58 (5.2%)	3
Nervous system disorders
Dizziness	8/62 (12.9%)	10	8/58 (13.8%)	11
Headache	8/62 (12.9%)	10	3/58 (5.2%)	4
Somnolence	1/62 (1.6%)	1	3/58 (5.2%)	3
Psychiatric disorders
Insomnia	7/62 (11.3%)	8	6/58 (10.3%)	6
Depression	2/62 (3.2%)	2	4/58 (6.9%)	5
Renal and urinary disorders
Dysuria	2/62 (3.2%)	3	4/58 (6.9%)	4
Haematuria	1/62 (1.6%)	2	3/58 (5.2%)	4
Acute kidney injury	0/62 (0%)	0	3/58 (5.2%)	3
Respiratory, thoracic and mediastinal disorders
Cough	21/62 (33.9%)	25	22/58 (37.9%)	31
Dyspnoea	15/62 (24.2%)	19	13/58 (22.4%)	15
Epistaxis	6/62 (9.7%)	6	13/58 (22.4%)	27
Productive cough	4/62 (6.5%)	5	6/58 (10.3%)	7
Nasal congestion	4/62 (6.5%)	5	5/58 (8.6%)	5
Oropharyngeal pain	6/62 (9.7%)	6	3/58 (5.2%)	3
Pleural effusion	5/62 (8.1%)	5	2/58 (3.4%)	2
Dyspnoea exertional	2/62 (3.2%)	2	3/58 (5.2%)	3
Skin and subcutaneous tissue disorders
Erythema	5/62 (8.1%)	6	4/58 (6.9%)	5
Pruritus	6/62 (9.7%)	6	1/58 (1.7%)	1
Petechiae	4/62 (6.5%)	4	1/58 (1.7%)	1
Vascular disorders
Haematoma	2/62 (3.2%)	2	7/58 (12.1%)	11
Hypotension	3/62 (4.8%)	4	6/58 (10.3%)	7
Hypertension	2/62 (3.2%)	2	4/58 (6.9%)	4
Pallor	1/62 (1.6%)	1	3/58 (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.