Trial Outcomes & Findings for 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) (NCT NCT02610777)

Last Updated: 2022-09-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

120 participants

Primary outcome timeframe

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

Results posted on

2022-09-19

Participant Flow

Participants took part in the study at 45 investigative sites in the United States \[US\], Canada, Belgium, Bulgaria, Czech Republic, Germany, France, Israel, Italy, Spain, and Ireland from 14 April 2016 to 23 July 2021.

Participants diagnosed with myelomonocytic, and myelogenous leukemia were randomized into two groups in 1:1 ratio to receive single-agent azacitidine or azacitidine + pevonedistat.

Participant milestones

Participant milestones
Measure	Azacitidine 75 mg/m^2 Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Overall Study STARTED	62	58
Overall Study Response Evaluable Population (REP)	53	55
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	62	58

Reasons for withdrawal

Reasons for withdrawal
Measure	Azacitidine 75 mg/m^2 Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Overall Study Lost to Follow-up	1	0
Overall Study Site Terminated by Sponsor	9	8
Overall Study Withdrawal by Subject	2	2
Overall Study Reason not Specified	0	1
Overall Study Death	50	47

Baseline Characteristics

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)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 n=120 Participants Total of all reporting groups
Age, Continuous	69.5 years STANDARD_DEVIATION 8.87 • n=5 Participants	71.7 years STANDARD_DEVIATION 9.63 • n=7 Participants	70.6 years STANDARD_DEVIATION 9.27 • n=5 Participants
Sex: Female, Male Female	21 Participants n=5 Participants	16 Participants n=7 Participants	37 Participants n=5 Participants
Sex: Female, Male Male	41 Participants n=5 Participants	42 Participants n=7 Participants	83 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	55 Participants n=5 Participants	52 Participants n=7 Participants	107 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) White	54 Participants n=5 Participants	52 Participants n=7 Participants	106 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Region of Enrollment Canada	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Region of Enrollment United States	27 Participants n=5 Participants	18 Participants n=7 Participants	45 Participants n=5 Participants
Region of Enrollment Belgium	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Region of Enrollment Bulgaria	5 Participants n=5 Participants	10 Participants n=7 Participants	15 Participants n=5 Participants
Region of Enrollment Czech Republic	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment Germany	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment Spain	8 Participants n=5 Participants	14 Participants n=7 Participants	22 Participants n=5 Participants
Region of Enrollment France	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment Ireland	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment Israel	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment Italy	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Height	169.12 centimeter (cm) STANDARD_DEVIATION 10.857 • n=5 Participants	168.87 centimeter (cm) STANDARD_DEVIATION 7.510 • n=7 Participants	169.00 centimeter (cm) STANDARD_DEVIATION 9.352 • n=5 Participants
Weight	79.19 kilogram (kg) STANDARD_DEVIATION 18.471 • n=5 Participants	75.95 kilogram (kg) STANDARD_DEVIATION 13.716 • n=7 Participants	77.62 kilogram (kg) STANDARD_DEVIATION 16.359 • n=5 Participants
Body Surface Area	1.92 square meter (m^2) STANDARD_DEVIATION 0.265 • n=5 Participants	1.88 square meter (m^2) STANDARD_DEVIATION 0.201 • n=7 Participants	1.90 square meter (m^2) STANDARD_DEVIATION 0.236 • n=5 Participants

PRIMARY outcome

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

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

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Overall Survival (OS)	19.0 months Interval 13.57 to 27.73	21.8 months Interval 18.53 to 30.88

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Event-Free Survival (EFS)	17.6 months Interval 11.96 to 20.5	21.0 months Interval 17.41 to 28.02

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=50 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=53 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Six-month Survival Rate	0.806 survival probability Interval 0.684 to 0.885	0.914 survival probability Interval 0.805 to 0.963

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=42 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=49 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
One-year Survival Rate	0.677 survival probability Interval 0.546 to 0.778	0.845 survival probability Interval 0.723 to 0.916

SECONDARY outcome

Timeframe: 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 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%.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=43 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=41 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Time to AML Transformation in HR MDS or CMML Participants	NA months The median and 95% confidence interval (CI) was not estimable as participants were censored.	NA months The median and 95% CI was not estimable as the participants were censored.

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=53 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=55 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Percentage of Participants With Complete Remission (CR)	36 percentage of participants	45 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=53 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=55 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Percentage of Participants With CR and Partial Remission (PR)	45 percentage of participants	51 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=53 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=55 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Percentage of Participants With Overall Response	62 percentage of participants	71 percentage of participants

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=15 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=17 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Percentage of Participants With CR in Low-blast AML	60.0 percentage of participants	41.2 percentage of participants

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=38 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=38 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Percentage of Participants With CR by Cycle 4	13.2 percentage of participants	26.3 percentage of participants

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=38 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=38 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Percentage of Participants With CR and PR by Cycle 4	21.1 percentage of participants	31.6 percentage of participants

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=38 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=38 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Percentage of Participants With Overall Response by Cycle 4	44.7 percentage of participants	57.9 percentage of participants

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=15 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=17 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Percentage of Participants With CR in Low-blast AML by Cycle 4	40.0 percentage of participants	35.3 percentage of participants

SECONDARY outcome

Timeframe: 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) 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).

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=19 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=25 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Duration of Complete Remission (CR)	12.9 months Interval 8.31 to The upper limit of full range was not estimable due to low number of participants with the event.	18.6 months Interval 9.0 to The upper limit of full range was not estimable due to low number of participants with the event.

SECONDARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=24 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=28 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Duration of Complete Remission (CR) and Partial Remission (PR)	12.9 months Interval 8.31 to The upper limit of 95% CI was not estimable due to low number of participants with the event.	18.6 months Interval 10.15 to The upper limit of 95% CI was not estimable due to low number of participants with the event.

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=33 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=39 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Duration of Overall Response	14.0 months Interval 12.62 to The upper limit of full range was not estimable due to lower number of participants with the event.	20.6 months Interval 10.71 to The upper limit of full range was not estimable due to lower number of participants with the event.

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=4 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=4 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Duration of Complete Remission (CR) in Low-blast AML	10.2 months Interval 0.2 to 10.2	12.6 months Interval 5.6 to 44.0

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=53 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=55 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Time to First CR or PR	13.2 months Interval 6.4 to The upper limit of 95% CI was not estimable due to low number of participants with the event.	8.3 months Interval 4.5 to The upper limit of 95% CI was not estimable due to low number of participants with the event.

SECONDARY outcome

Timeframe: From date of randomization 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Time to Subsequent Therapy	NA months The median and 95% CI was not estimable due to low number of participants with the event.	NA months The median and 95% CI was not estimable due to lower number of participants with the event.

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=26 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=26 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence RBCs-transfusion Independence	50.0 percentage of participants	69.2 percentage of participants
Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence Platelet-transfusion Independence	60.0 percentage of participants	80.0 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Percentage of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML	0.4811 percentage of participants Interval 0.37956 to 0.58265	0.5878 percentage of participants Interval 0.42606 to 0.74953

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Time to Progressive Disease (PD), Relapse, or Death	13.6 months Interval 9.4 to 16.53	15.2 months Interval 12.39 to 20.83

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	62 Participants	57 Participants
Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	40 Participants	40 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Number of Participants in the Safety Analysis Population With Clinically Significant Laboratory Abnormalities Reported as TEAEs Neutropenia	21 Participants	21 Participants
Number of Participants in the Safety Analysis Population With Clinically Significant Laboratory Abnormalities Reported as TEAEs Anaemia	29 Participants	19 Participants
Number of Participants in the Safety Analysis Population With Clinically Significant Laboratory Abnormalities Reported as TEAEs Neutrophil count decreased	6 Participants	12 Participants
Number of Participants in the Safety Analysis Population With Clinically Significant Laboratory Abnormalities Reported as TEAEs Thrombocytopenia	15 Participants	16 Participants

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline: 0; Overall: 0	13 Participants	9 Participants
Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline: 0; Overall: 1	15 Participants	13 Participants
Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline: 0; Overall: 2	3 Participants	3 Participants
Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline: 0; Overall: 3	0 Participants	2 Participants
Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline: 0; Overall: 4	2 Participants	0 Participants
Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline: 1; Overall: 1	17 Participants	18 Participants
Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline: 1; Overall: 2	5 Participants	8 Participants
Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline: 1; Overall: 3	5 Participants	2 Participants
Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline: 2; Overall: 2	2 Participants	3 Participants

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values Reported as TEAEs Atrial fibrillation	4 Participants	4 Participants
Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values Reported as TEAEs Tachycardia	1 Participants	4 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=62 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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 + Pevonedistat 20 mg/m^2 n=58 Participants Azacitidine 75 mg/m\^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, 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).
Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline Values in Vital Signs Reported as TEAEs Pyrexia	25 Participants	22 Participants
Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline Values in Vital Signs Reported as TEAEs Hypotension	3 Participants	6 Participants

Adverse Events

Azacitidine 75 mg/m^2

Serious events: 40 serious events

Other events: 58 other events

Deaths: 50 deaths

Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2

Serious events: 40 serious events

Other events: 51 other events

Deaths: 47 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER