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)

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. The Kaplan Meier estimates was used for the analysis.

Time frame: From date of randomization until death (up to 3 years and 5 months)

Population: ITT Population was defined as all participants who were randomized.

Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML) or relapse after CR or PR (participants with HR MDS/CMML). Disease responses for HR MDS or CMML are based on the Modified IWG Response Criteria for MDS and for low-blast AML on the Revised IWG Response Criteria for AML.CR for HR MDS or CMML≤5% myeloblasts with normal maturation of all cell lines in the bone marrow,≥11 g/dL Hgb,≥100\*10\^9/L pl,≥1.0\*10\^9/L neutrophils;0% blasts in peripheral blood.CR for low-blast AML:morphologic leukemia-free state,neutrophils of\<1.0\*10\^9/L;pl of≥100\*10\^9/L,transfusion independence,no residual evidence of extramedullary leukemia.CRi for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (\<1.0\*10\^9/L) or thrombocytopenia (pl\<100\*10\^9/L).

Time frame: From date of randomization until CR (up to approximately 5 years)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for the responders with complete remission.

Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML). 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.

Time frame: From date of randomization until CR or PR (up to approximately 5 years)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for the responders with complete CR and PR.

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).

Time frame: From date of randomization until CR (up to approximately 5 years)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for responders with low blast AML having complete remission.

Duration of OR: response to first documentation of PD or relapse from CR for low-blast AML or relapse after CR or PR for HR MDS/CMML. Disease responses(HR MDS/CMML): modified IWG criteria for MDS;low-blast AML: revised IWG criteria for AML.Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ Cri+PR.HR MDS/CMML-CR:≤5%myeloblasts with normal maturation of 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.

Time frame: From date of randomization until CR, PR or HI (up to approximately 5 years)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for overall responders.

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. The Kaplan-Meier estimate was used for the analysis.

Time frame: From date of randomization until transformation to AML, or death due to any cause (up to approximately 5 years)

Population: ITT Population was defined as all participants who were randomized.

ECG assessments included QT, QRS duration, PR interval, ventricular rate, QTcB, QTcF.

Time frame: From date of first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)

Population: Safety Population included all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.

Vital signs assessments included diastolic and systolic blood pressure, heart rate, and body temperature.

Time frame: From date of first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)

Population: Safety Population included all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.

Laboratory assessments included clinical chemistry, hematology, and urinalysis.

Time frame: From date of first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)

Population: Safety Population included all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.

An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. A SAE was defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is an medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization. A TEAE was defined as any adverse event occurring after the start of pevonedistat administration of the treatment period.

Time frame: From date of first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)

Population: Safety Population included all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.

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).

Time frame: From date of first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)

Population: ITT population was defined as all participants who were randomized in the Safety Population. Only categories for which there was at least 1 participant are reported.

Kaplan-Meier estimate of probability of OS at the end of the first year from randomization.

Time frame: Month 12

Population: ITT Population was defined as all participants who were randomized. Overall number analyzed are the number of participants with data available for analyses.

Inpatient hospital admission data was collected through transformation to AML (HR MDS/CMML participants) or disease progression (low-blast AML participants) or until initiation of subsequent therapy (all participants), whichever occurred first. Transformation to AML is defined, according to WHO Classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%. Percentage of participants was calculated as the total number of events divided by the total number of subject-years in each group.

Time frame: From date of randomization until transformation to AML or until initiation of subsequent therapy (up to approximately 5 years)

Population: ITT Population included all participants who were randomized.

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: \<= 5% myeloblasts with normal maturation of all cell lines in the bone marrow, and \>= 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). The percentages are rounded off to report the nearest whole numbers.

Time frame: From date of randomization until CR (up to approximately 5 years)

Population: Response-Evaluable Population (REP) included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.

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. The percentages are rounded off to report the nearest whole numbers.

Time frame: From date of randomization until CR and PR (up to approximately 5 years)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.

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. The percentages are rounded off to report the nearest whole numbers.

Time frame: From date of randomization until CR and PR, by Cycle 4 (cycle length=28 days)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Overall number analyzed is the number of participants with data available for analyses.

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). The percentages are rounded off to report the nearest whole numbers.

Time frame: From date of randomization until CR by Cycle 4 (cycle length is equal to [=] 28 days)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Overall number analyzed is the number of participants with data available for analyses.

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). The percentages are rounded off to report the nearest whole numbers.

Time frame: From date of randomization until CR (up to approximately 5 years)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Overall number analyzed are the number of participants with data available for analyses.

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). The percentages are rounded off to report the nearest whole numbers.

Time frame: From the date of randomization until CR by Cycle 4 (cycle length=28 days)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for low blast AML participants which is included as the overall number of participants analyzed.

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. The percentages are rounded off to report the nearest whole numbers.

Time frame: From date of randomization until CR, PR, or hematologic improvement (HI) (up to approximately 5 years)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.

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. The percentages are rounded off to report the nearest whole numbers.

Time frame: From date of randomization until CR, PR or HI, by Cycle 4 (cycle length=28 days)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Overall number analyzed is the number of participants with data available for analyses.

A participant was defined as RBC or platelet-transfusion independent if he/she received no RBC or platelet transfusions for a period of at least 8 weeks before the first dose of study drug through 30 days after the last dose of any study drug. Rate of transfusion independence was defined as number of participants who became transfusion independent divided by the number of participants who were transfusion dependent at Baseline.

Time frame: 8 weeks before randomization through 30 days after last dose of any study drug (up to approximately 5 years and 3 months)

Population: ITT Population included all participants who were randomized. Overall number analyzed are the number of participants from a subset of the ITT Population who were transfusion dependent at Baseline. Number analyzed is the number of participants who were transfusion dependent at Baseline for the specified category.

Kaplan-Meier estimate of probability of OS at the end of the month 6 from randomization.

Time frame: Month 6

Population: ITT Population was defined as all participants who were randomized. Overall number analyzed are the number of participants with data available for analyses.

Time to AML transformation in HR MDS and CMML participants is defined as time from randomization to documented AML transformation. Participants without documented AML transformation at the time of the analysis are censored at the date of the last assessment. Participants who died before progression to AML are censored at the date of death. 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%.

Time frame: From date of randomization until transformation to AML (up to approximately 5 years)

Population: ITT Population was defined as all participants who were randomized. Overall number of participants analyzed is the number of participants with data available for analyses.

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.

Time frame: From date of randomization until CR or PR (up to approximately 5 years)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.

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.

Time frame: From date of randomization until PD, relapse or death (up to approximately 5 years)

Population: ITT Population was defined as all participants who were randomized.

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 did not be counted as receiving subsequent therapy.

Time frame: From date of randomization up to approximately 5 years

Population: ITT Population was defined as all participants who were randomized.