Trial Outcomes & Findings for Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML) (NCT NCT03268954)

Last Updated: 2025-10-29

Results Overview

EFS was defined as the time from randomization to the date of an EFS event. An EFS event was defined as death or transformation to acute myelogenous leukemia (AML) (World Health Organization \[WHO\] classification as a participant having greater than 20 % blasts in the blood or marrow and an increase of blast count by 50%), whichever event occurred first, in participants with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemias (CMML). An EFS event was defined as death in participants with low-blast AML.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

454 participants

Primary outcome timeframe

From randomization until transformation to acute myeloid leukemia, or death due to any cause: up to approximately 42 months

Results posted on

2025-10-29

Participant Flow

Participants took part in the study at 130 investigative sites globally from 28 November 2017 to 14 October 2024.

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 Participants were administered azacitidine 75 milligram per square meter (mg/m\^2) intravenous (IV) or subcutaneous (SC) injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Overall Study STARTED	227	227
Overall Study Safety Population	220	223
Overall Study COMPLETED	195	199
Overall Study NOT COMPLETED	32	28

Reasons for withdrawal

Reasons for withdrawal
Measure	Azacitidine 75 mg/m^2 Participants were administered azacitidine 75 milligram per square meter (mg/m\^2) intravenous (IV) or subcutaneous (SC) injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Overall Study Withdrawal by Subject	27	17
Overall Study Lost to Follow-up	2	3
Overall Study Reason Not Specified	3	8

Baseline Characteristics

ITT Population included all participants who were randomized. Number analyzed is the number of participants with data available for height at Baseline.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Total n=454 Participants Total of all reporting groups
Age, Continuous	73.0 years STANDARD_DEVIATION 8.22 • n=227 Participants	73.0 years STANDARD_DEVIATION 7.65 • n=227 Participants	73 years STANDARD_DEVIATION 7.93 • n=454 Participants
Sex: Female, Male Female	85 Participants n=227 Participants	95 Participants n=227 Participants	180 Participants n=454 Participants
Sex: Female, Male Male	142 Participants n=227 Participants	132 Participants n=227 Participants	274 Participants n=454 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	26 Participants n=227 Participants	31 Participants n=227 Participants	57 Participants n=454 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	188 Participants n=227 Participants	189 Participants n=227 Participants	377 Participants n=454 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	13 Participants n=227 Participants	7 Participants n=227 Participants	20 Participants n=454 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=227 Participants	4 Participants n=227 Participants	6 Participants n=454 Participants
Race (NIH/OMB) Asian	20 Participants n=227 Participants	31 Participants n=227 Participants	51 Participants n=454 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=227 Participants	0 Participants n=227 Participants	0 Participants n=454 Participants
Race (NIH/OMB) Black or African American	1 Participants n=227 Participants	2 Participants n=227 Participants	3 Participants n=454 Participants
Race (NIH/OMB) White	189 Participants n=227 Participants	180 Participants n=227 Participants	369 Participants n=454 Participants
Race (NIH/OMB) More than one race	0 Participants n=227 Participants	0 Participants n=227 Participants	0 Participants n=454 Participants
Race (NIH/OMB) Unknown or Not Reported	15 Participants n=227 Participants	10 Participants n=227 Participants	25 Participants n=454 Participants
Region of Enrollment Australia	3 Participants n=227 Participants	4 Participants n=227 Participants	7 Participants n=454 Participants
Region of Enrollment Belgium	8 Participants n=227 Participants	3 Participants n=227 Participants	11 Participants n=454 Participants
Region of Enrollment Brazil	10 Participants n=227 Participants	18 Participants n=227 Participants	28 Participants n=454 Participants
Region of Enrollment China	2 Participants n=227 Participants	0 Participants n=227 Participants	2 Participants n=454 Participants
Region of Enrollment Czech Republic	10 Participants n=227 Participants	6 Participants n=227 Participants	16 Participants n=454 Participants
Region of Enrollment Germany	6 Participants n=227 Participants	3 Participants n=227 Participants	9 Participants n=454 Participants
Region of Enrollment Spain	26 Participants n=227 Participants	23 Participants n=227 Participants	49 Participants n=454 Participants
Region of Enrollment France	13 Participants n=227 Participants	8 Participants n=227 Participants	21 Participants n=454 Participants
Region of Enrollment United Kingdom	1 Participants n=227 Participants	3 Participants n=227 Participants	4 Participants n=454 Participants
Region of Enrollment Greece	30 Participants n=227 Participants	28 Participants n=227 Participants	58 Participants n=454 Participants
Region of Enrollment Israel	6 Participants n=227 Participants	6 Participants n=227 Participants	12 Participants n=454 Participants
Region of Enrollment Italy	14 Participants n=227 Participants	9 Participants n=227 Participants	23 Participants n=454 Participants
Region of Enrollment Japan	12 Participants n=227 Participants	26 Participants n=227 Participants	38 Participants n=454 Participants
Region of Enrollment Korea, Republic of	4 Participants n=227 Participants	2 Participants n=227 Participants	6 Participants n=454 Participants
Region of Enrollment Poland	11 Participants n=227 Participants	10 Participants n=227 Participants	21 Participants n=454 Participants
Region of Enrollment Russia	22 Participants n=227 Participants	12 Participants n=227 Participants	34 Participants n=454 Participants
Region of Enrollment Turkey	5 Participants n=227 Participants	5 Participants n=227 Participants	10 Participants n=454 Participants
Region of Enrollment Canada	2 Participants n=227 Participants	7 Participants n=227 Participants	9 Participants n=454 Participants
Region of Enrollment Mexico	2 Participants n=227 Participants	5 Participants n=227 Participants	7 Participants n=454 Participants
Region of Enrollment United States of America	40 Participants n=227 Participants	49 Participants n=227 Participants	89 Participants n=454 Participants
Height	167.59 centimeter (cm) STANDARD_DEVIATION 9.439 • n=225 Participants • ITT Population included all participants who were randomized. Number analyzed is the number of participants with data available for height at Baseline.	166.31 centimeter (cm) STANDARD_DEVIATION 10.098 • n=223 Participants • ITT Population included all participants who were randomized. Number analyzed is the number of participants with data available for height at Baseline.	166.95 centimeter (cm) STANDARD_DEVIATION 9.783 • n=448 Participants • ITT Population included all participants who were randomized. Number analyzed is the number of participants with data available for height at Baseline.
Weight	77.65 kilogram (kg) STANDARD_DEVIATION 16.143 • n=227 Participants • ITT Population included all participants who were randomized. Number analyzed is the number of participants with data available for weight at Baseline.	75.82 kilogram (kg) STANDARD_DEVIATION 15.996 • n=226 Participants • ITT Population included all participants who were randomized. Number analyzed is the number of participants with data available for weight at Baseline.	76.73 kilogram (kg) STANDARD_DEVIATION 16.078 • n=453 Participants • ITT Population included all participants who were randomized. Number analyzed is the number of participants with data available for weight at Baseline.
Body Surface Area	1.89 meter square (m^2) STANDARD_DEVIATION 0.228 • n=225 Participants • ITT Population included all participants who were randomized. Number analyzed is the number of participants with data available for body surface area at Baseline.	1.86 meter square (m^2) STANDARD_DEVIATION 0.233 • n=223 Participants • ITT Population included all participants who were randomized. Number analyzed is the number of participants with data available for body surface area at Baseline.	1.88 meter square (m^2) STANDARD_DEVIATION 0.231 • n=448 Participants • ITT Population included all participants who were randomized. Number analyzed is the number of participants with data available for body surface area at Baseline.

PRIMARY outcome

Timeframe: From randomization until transformation to acute myeloid leukemia, or death due to any cause: up to approximately 42 months

Population: ITT Population included all participants who were randomized.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Event-Free Survival (EFS)	15.7 months Interval 14.42 to 19.68	17.7 months Interval 13.63 to 20.24

SECONDARY outcome

Timeframe: Up to approximately 6.9 years

Population: ITT Population included all participants who were randomized.

Overall survival was defined as the time from randomization to death from any cause.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Overall Survival (OS)	16.8 months Interval 14.92 to 20.11	20.3 months Interval 17.97 to 22.6

SECONDARY outcome

Timeframe: Month 6

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

Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of Month 6 from randomization are presented.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=174 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=174 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Kaplan-Meier Estimates of Six-Month Survival Rate	0.825 percentage probability Interval 0.767 to 0.869	0.810 percentage probability Interval 0.752 to 0.856

SECONDARY outcome

Timeframe: Year 1

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

Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of the first year from randomization are presented.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=141 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=137 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Kaplan-Meier Estimates of One-Year Survival Rate	0.693 percentage probability Interval 0.626 to 0.751	0.646 percentage probability Interval 0.578 to 0.706

SECONDARY outcome

Timeframe: Up to Day 30

Population: Safety Population included all enrolled participants who received at least 1 dose of azacitidine alone or pevonedistat + azacitidine.

30-day mortality was defined as number of participants who died within 30 days from the first dose of study drug.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=220 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=223 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30	6 Participants	5 Participants

SECONDARY outcome

Timeframe: Up to Day 60

Population: Safety Population included all enrolled participants who received at least 1 dose of azacitidine alone or pevonedistat + azacitidine.

60-day mortality was defined as number of participants who died within 60 days from the first dose of study drug.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=220 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=223 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60	15 Participants	14 Participants

SECONDARY outcome

Timeframe: From randomization until transformation to AML (up to approximately 42 months)

Population: ITT Population included all participants who were randomized. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis for the given category.

Time to AML transformation in HR MDS and CMML participants was defined as time from randomization to documented AML transformation as determined by the independent review committee (IRC) assessment. Participants who died before progression to AML were censored. Transformation to AML was defined, according to 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=174 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=177 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants HR MDS Participants	35.6 months Interval 26.51 to The upper limit of 95% confidence interval (CI) was not estimable due to low number of participants with event.	NA months Interval 23.29 to The median, and upper limit of 95% CI were not estimable due to low number of participants with event.
Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants HR CMML Participants	NA months The median, lower limit, and upper limit of 95% CI were not estimable due to low number of participants with event.	NA months The median, lower limit, and upper limit of 95% CI were not estimable due to low number of participants with event.
Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants HR MDS/CMML Participants	35.6 months Interval 29.04 to The upper limit of 95% CI was not estimable due to low number of participants with event.	NA months Interval 24.28 to The median, and upper limit of 95% CI were not estimable due to low number of participants with event.

SECONDARY outcome

Timeframe: From randomization until CR (up to approximately 42 months)

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.

CR for HR MDS or CMML is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to \>=11 gram per deciliter (g/dL) hemoglobin (Hgb),\>=100\*10\^9/liter (/L) platelets (pl),\>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0\*10\^9/L and pl of \>=100\*10\^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (\<1.0\*10\^9/L) or thrombocytopenia (pl\<100\*10\^9/L).

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=206 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=208 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi)	71 Participants	63 Participants

SECONDARY outcome

Timeframe: From randomization until CR or marrow CR (up to approximately 42 months)

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 are based on the International Working Group (IWG) Response Criteria for MDS. CR for HR MDS or CMML is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and \>=11 g/dL Hgb, \>=100\*10\^9/L platelets (pl), \>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=206 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=208 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With CR and Marrow CR	91 Participants	87 Participants

SECONDARY outcome

Timeframe: From randomization until, CR, PR or HI (up to approximately 42 months)

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 based on Modified IWG Response Criteria for MDS. CR: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment. PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still \>5%. HI: Hgb increase \>=1.5 g/dL if \<11 g/dL; pl increase \>=30\*10\^9/L if baseline\>20\*10\^9/L or increase from \<20\*10\^9/L to \>20\*10\^9/L and by at least 100%; neutrophil increase by 100% and absolute increase of \>0.5\*10\^9/L if baseline \<1.0\*10\^9/L.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=206 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=208 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI)	77 Participants	76 Participants

SECONDARY outcome

Timeframe: From randomization until CR or Marrow CR and PR (up to approximately 42 months)

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.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=206 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=208 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With CR and Marrow CR and PR	91 Participants	87 Participants

SECONDARY outcome

Timeframe: From randomization until CR, marrow CR, PR or HI (up to approximately 42 months)

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 based on Modified IWG Response Criteria for MDS. CR: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment. PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still\>5%. HI: Hgb increase \>=1.5 g/dL if baseline \<11 g/dL; pl increase \>=30\*10\^9/L if baseline\>20\*10\^9/L or increases from \<20\*10\^9/L to \>20\*10\^9/L and by at least 100%; neutrophil increases by 100% and absolute increases of \>0.5\*10\^9/L if baseline \<1.0\*10\^9/L.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=206 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=208 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI)	112 Participants	117 Participants

SECONDARY outcome

Timeframe: From randomization until CR and PR or CR, CRi and PR (up to approximately 42 months)

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 based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR or PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still\>5%. For low-blast AML-CR:morphologic leukemia-free state\>1.0\*10\^9 neutrophils, \>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L or pl \<100\*10\^9/L; PR: all CR hematological values but \>=50% decrease in bone marrow aspirate.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=206 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=208 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With Overall Response (OR)	73 Participants	64 Participants

SECONDARY outcome

Timeframe: From randomization until, CR, PR or HI or CR, CRi or PR (up to approximately 42 months)

Population: REP: 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. Three participants were not counted as responders for OR2 as the IRC assessed these participants as non-responders.

OR2=participant with best overall response of CR+PR+HI in HR MDS/CMML participants,or of CR+CRi+PR in low-blast AML participants.CR:≤5% myeloblasts with normal maturation of all bone marrow(BM)cell lines,≥11g/dL Hgb,≥100\*10\^9/L pl,≥1.0\*10\^9/L neutrophils,0% blasts in peripheral blood;PR:all CR criteria met except BM blasts ≥50% decrease over pretreatment but still \>5%;HI:Hgb increase(inc) ≥1.5g/dL if baseline(BL)\<11 g/dL;pl inc≥30\*10\^9/L if BL\>20\*10\^9/L or inc from \<20\*10\^9/L to \>20\*10\^9/L and by 100%;neutrophil inc by 100%;absolute inc of \>0.5\*10\^9/L if BL\<100\*10\^9/L.For low-blast AML-CR:morphologic leukemia-free state \>1.0\*10\^9 neutrophils,≥100\*10\^9/L pl,transfusion independence,no residual evidence of extramedullary leukemia;CR with incomplete blood count recovery:fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L or pl\<100\*10\^9/L;PR:all CR hematological values but ≥50% decrease in BM aspirate.Number of responders determined by independent review committee(IRC) assessment.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=206 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=208 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With Overall Response 2 (OR2)	94 Participants	94 Participants

SECONDARY outcome

Timeframe: From CR until first documentation of PD or relapse from CR or relapse after CR or PR (up to approximately 42 months)

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 participants 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 is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to \>=11 g/dL Hgb,\>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0\*10\^9/L and pl of \>=100\*10\^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (\<1.0\*10\^9/L) or thrombocytopenia (pl\<100\*10\^9/L).

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=68 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=57 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Duration of Complete Remission (CR)	13.1 months Interval 6.93 to 29.08	17.2 months Interval 13.96 to The upper limit of 95% CI was not estimable due to low number of participants with event.

SECONDARY outcome

Timeframe: From CR until first documentation of PD or relapse from CR or relapse after CR or PR (up to approximately 42 months)

Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML). Disease responses for low-blast AML were based on the Revised IWG Response Criteria for AML. CR is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to \>=11 g/dL hemoglobin (Hgb),\>=100\*10\^9/liter (/L) platelets (pl),\>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0\*10\^9/L and pl of \>=100\*10\^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (\<1.0\*10\^9/L) or thrombocytopenia (pl\<100\*10\^9/L).

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=15 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=17 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi)	8.5 months Interval 3.02 to The upper limit of 95% CI was not estimable due to low number of participants with event.	15.0 months Interval 3.94 to The upper limit of 95% CI was not estimable due to low number of participants with event.

SECONDARY outcome

Timeframe: Up to approximately 42 months

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.

Duration of OR: response to first documentation of PD or relapse from CR for low-blast AML or relapse after CR or PR for HR MDS/CMML. Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR+PR for HR MDS/CMML and CR+Cri+ PR for low-blast AML.CR for HR MDS/CMML:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11 g/dL Hgb,\>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood and PR:all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment but still \>5%. For low-blast AML-CR: morphologic leukemia-free state \>1.0\*10\^9 neutrophils,\>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with CRi: fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L or pl \<100\*10\^9/L; PR: all CR hematological values but \>=50% decrease in % of blasts in bone marrow aspirate.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=73 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=64 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Duration of Overall Response (OR)	18.3 months Interval 8.31 to The upper limit of 95% CI was not estimable due to low number of participants with event.	17.1 months Interval 12.68 to The upper limit of 95% CI was not estimable due to low number of participants with event.

SECONDARY outcome

Timeframe: Up to approximately 42 months

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. Three participants who were non-responders (for OR2) as per the IRC were included in this outcome measure as they had assessment of HI and duration of OR2 for these participants could still be derived based on the pre-specified criteria for HR MDS/CMML participants.

Duration of OR2: from date of first documentation of CR+PR+HI to first documentation of PD/relapse after CR/PR for responders of CR+PR+HI for HR MDS/CMML and CR,CRi,PR for low-blast AML. For HR MDS/CMML-CR:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11 g/dL Hgb, \>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment, still \>5%; HI:Hgb inc \>=1.5 g/dL if baseline \<11 g/dL; pl inc\>=30\*10\^9/L if baseline\>20\*10\^9/L or inc from\<20\*10\^9/L to\>20\*10\^9/L by at least 100%; neutrophil inc by 100% and absolute inc of \>0.5\*10\^9/L if baseline \<1.0\*10\^9/L.For low-blast AML-CR: morphologic leukemia-free state,\>1.0\*10\^9 neutrophils,\>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia;CRi: fulfill CR criteria except residual neutropenia\<1.0\*10\^9/L or pl \<100\*10\^9/L;PR:all CR hematological values but\>=50% decrease in bone marrow aspirate.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=95 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=96 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Duration of Overall Response 2 (OR2)	18.3 months Interval 11.17 to 30.92	18.9 months Interval 15.01 to The upper limit of 95% CI was not estimable due to lower number of participants with the event.

SECONDARY outcome

Timeframe: Up to approximately 42 months

Population: ITT Population included all participants who were randomized. Overall number analyzed is 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=140 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=129 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence Percentage of Participants With RBCs-transfusion Independence	44.3 percentage of participants	47.5 percentage of participants
Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence Percentage of Participants With Platelet-transfusion Independence	48.9 percentage of participants	45.5 percentage of participants

SECONDARY outcome

Timeframe: Up to approximately 42 months

Population: ITT Population included all participants who were randomized. Number analyzed is the number of participants who achieved transfusion independence for the specified category, with data available for analysis.

Duration of RBC and platelet transfusion independence was defined as the longest time between the last RBC and/or platelet transfusion before the start of the RBC and/or platelet transfusion-independent period and the first RBC and/or platelet transfusion after the start of the transfusion-independent period, which occurs \>= 8 weeks later.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence Duration of RBC Transfusion Independence	15.6 months Interval 10.18 to 28.09	13.5 months Interval 9.07 to 16.66
Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence Duration of Platelet Transfusion Independence	14.9 months Interval 5.09 to 23.23	11.6 months Interval 2.73 to 16.26
Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence Duration of Transfusion Independence	12.0 months Interval 8.9 to 19.48	13.5 months Interval 10.38 to 16.66

SECONDARY outcome

Timeframe: From randomization until CR or PR (up to approximately 42 months)

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 is defined as the time from randomization to first documented CR or PR, whichever occurs first. Disease responses for HR MDS or CMML or low-blast AML cycle 6 are based on Modified IWG Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. For HR MDS or CMML-CR:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11 g/dL Hgb,\>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment but still\>5%; For low-blast AML-CR: morphologic leukemia-free state,\>1.0\*10\^9/L neutrophils, pl\>=100\*10\^9/L, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery: fulfill CR criteria except residual neutropenia\<1.0\*10\^9/L or pl \<100\*10\^9/L; PR: all CR hematological values but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=206 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=208 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi)	NA months Interval 12.12 to The median, and upper limit of 95% CI was not estimable due to low number of participants with event.	NA months Interval 24.61 to The median, and upper limit of 95% CI was not estimable due to low number of participants with event.

SECONDARY outcome

Timeframe: From randomization until HI (up to approximately 42 months)

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/CMML based on Modified IWG Response Criteria for MDS. HI: Hgb increase \>=1.5 g/dL if baseline \<11 g/dL; pl increase \>=30\*10\^9/L if baseline \>20\*10\^9/L or increase from \<20\*10\^9/L to \>20\*10\^9/L by at least 100%; neutrophil increase by 100% and absolute increase of \>0.5\*10\^9/L if baseline \<1.0\*10\^9/L.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=157 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=163 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With Hematologic Improvement (HI)	76 Participants	70 Participants

SECONDARY outcome

Timeframe: From randomization until transformation to AML or until initiation of subsequent therapy (up to approximately 42 months)

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%.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML	3 Participants	9 Participants

SECONDARY outcome

Timeframe: From randomization until PD, relapse after CR, or relapse after CR or PR, or death due to any cause, whichever occurs first (up to approximately 42 months)

Population: ITT Population included all participants who were randomized.

Time to PD, relapse after CR(low-blast AML), relapse after CR or PR(HR MDS/CMML), or death,defined as time from date of randomization until date of first documentation of PD,relapse after CR(low-blast AML),relapse after CR or PR(HR MDS/CMML),or death due to any cause, whichever occurs first. In HR MDS/CMML,PD: Participants with\<5% blasts:\>=50% inc \>5% blasts, with 5%-9% blasts:\>=50% inc\>10% blasts, with 10%-19% blasts:\>=50% inc \>20% blasts,with 20%-30% blasts, at least 50% decrement from maximum remission/response in granulocytes or pl or reduction in Hgb by\>=2 g/dL/new transfusion dependence.Relapse after CR or PR: return to pretreatment bone marrow blast %/Decrement of \>=50% from maximum remission/response levels in granulocytes/pl/reduction in Hgb conc.\>=1.5 g/dL/transfusion dependence. In AML,PD:\>50% inc in bone marrow blasts to \>30% blasts,\>50% inc in circulating blasts to\>30% blasts in peripheral blood, Development of extramedullary disease/new sites of extramedullary leukemia.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death	11.8 months Interval 10.25 to 13.31	13.1 months Interval 11.01 to 15.84

SECONDARY outcome

Timeframe: Baseline, at approximately 58 months

Population: ITT Population included all participants who were randomized. All participants with PRO measurements at baseline and with data available at end of treatment were analyzed for this outcome measure.

The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. Most of the 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QOL scale, higher scores represent better QOL; for the symptom scales, lower scores represent better QOL. The change from baseline at end of treatment is reported.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=211 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=210 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Nausea/Vomiting Score: Baseline	4.6 score on a scale Standard Deviation 11.39	4.7 score on a scale Standard Deviation 10.96
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Financial Difficulties Score: Baseline	14.2 score on a scale Standard Deviation 25.37	18.4 score on a scale Standard Deviation 26.76
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Financial Difficulties Score: Change from Baseline	5.9 score on a scale Standard Deviation 27.03	7.4 score on a scale Standard Deviation 30.46
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Global Health Status/QoL Score: Baseline	60.3 score on a scale Standard Deviation 22.11	61.6 score on a scale Standard Deviation 21.13
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Physical Functioning Score: Baseline	69.4 score on a scale Standard Deviation 22.63	75.7 score on a scale Standard Deviation 20.38
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Global Health Status/QoL Score: Change from Baseline	-3.0 score on a scale Standard Deviation 25.93	-8.4 score on a scale Standard Deviation 26.89
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Physical Functioning Score: Change from Baseline	-7.5 score on a scale Standard Deviation 22.82	-13.4 score on a scale Standard Deviation 27.51
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Cognitive Functioning Score: Change from Baseline	-7.2 score on a scale Standard Deviation 22.65	-10.4 score on a scale Standard Deviation 24.38
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Cognitive Functioning Score: Baseline	84.6 score on a scale Standard Deviation 18.29	86.1 score on a scale Standard Deviation 17.60
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Social Functioning Score: Baseline	79.3 score on a scale Standard Deviation 25.37	78.8 score on a scale Standard Deviation 25.82
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Social Functioning Score: Change from Baseline	-13.7 score on a scale Standard Deviation 33.89	-16.5 score on a scale Standard Deviation 34.78
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Role Functioning Score: Baseline	66.9 score on a scale Standard Deviation 30.88	73.7 score on a scale Standard Deviation 28.55
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Role Functioning Score: Change from Baseline	-11.8 score on a scale Standard Deviation 35.41	-18.3 score on a scale Standard Deviation 36.72
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Emotional Functioning Score: Baseline	76.0 score on a scale Standard Deviation 20.96	77.6 score on a scale Standard Deviation 22.10
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Emotional Functioning Score: Change from Baselline	-2.5 score on a scale Standard Deviation 23.80	-5.9 score on a scale Standard Deviation 22.41
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Nausea/Vomiting Score: Change from Baseline	2.4 score on a scale Standard Deviation 19.08	1.9 score on a scale Standard Deviation 15.00
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Fatigue Score: Baseline	38.5 score on a scale Standard Deviation 25.44	33.8 score on a scale Standard Deviation 24.24
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Fatigue Score: Change from Baseline	6.6 score on a scale Standard Deviation 26.41	12.3 score on a scale Standard Deviation 31.22
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 QLQ-C30 Summary Score: Change from Baseline	-6.1 score on a scale Standard Deviation 18.84	-8.6 score on a scale Standard Deviation 17.75
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Pain Score: Baseline	20.9 score on a scale Standard Deviation 25.55	19.4 score on a scale Standard Deviation 26.42
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Pain Score: Change from Baseline	5.8 score on a scale Standard Deviation 30.36	6.8 score on a scale Standard Deviation 33.34
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Dyspnoea Score: Baseline	25.4 score on a scale Standard Deviation 29.83	24.4 score on a scale Standard Deviation 28.90
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Dyspnoea Score: Change from Baseline	5.9 score on a scale Standard Deviation 28.95	5.9 score on a scale Standard Deviation 29.46
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Insomnia Score: Baseline	27.2 score on a scale Standard Deviation 27.96	25.7 score on a scale Standard Deviation 30.68
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Insomnia Score: Change from Baseline	3.2 score on a scale Standard Deviation 34.32	4.6 score on a scale Standard Deviation 34.09
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Appetite Loss Score: Baseline	23.4 score on a scale Standard Deviation 29.29	15.6 score on a scale Standard Deviation 23.99
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Appetite Loss Score: Change from Baseline	4.6 score on a scale Standard Deviation 38.68	16.0 score on a scale Standard Deviation 34.03
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Constipation Score: Baseline	14.7 score on a scale Standard Deviation 24.78	13.8 score on a scale Standard Deviation 22.47
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Constipation Score: Change from Baseline	5.5 score on a scale Standard Deviation 29.56	5.1 score on a scale Standard Deviation 28.42
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Diarrhoea Score: Baseline	7.6 score on a scale Standard Deviation 18.84	7.0 score on a scale Standard Deviation 16.75
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Diarrhoea Score: Change from Baseline	3.0 score on a scale Standard Deviation 22.80	1.9 score on a scale Standard Deviation 27.65
Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 QLQ-C30 Summary Score: Baseline	77.9 score on a scale Standard Deviation 14.90	80.5 score on a scale Standard Deviation 15.08

SECONDARY outcome

Timeframe: From randomization until CR, CRi and PR (up to approximately 42 months)

Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR + PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment but still\>5%. For low-blast AML-CR: morphologic leukemia-free state, \>1.0\*10\^9 neutrophils,\>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia\<1.0\*10\^9/L or pl\<100\*10\^9/L; PR: all CR hematological values but\>=50% decrease in the percentage of blasts to 5% to 25% in bone marrow aspirate.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=52 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=54 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With Overall Response in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group OR: HR MDS/CMML Participants	14 Participants	13 Participants
Number of Participants With Overall Response in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group OR: Low-blast AML Participants	13 Participants	12 Participants

SECONDARY outcome

Timeframe: From randomization until transformation to AML if eligible or death (up to approximately 42 months)

Population: ITT Population included all participants who were randomized.

Event was defined as death or transformation to AML in participants with MDS or CMML, whichever occurred first. Transformation to AML was defined, according to World Health Organization (WHO) Classification as a participant having \>20% blasts in the blood or marrow and increase of blast count by 50%. Event was defined as death in participants with low-blast AML.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group	12.8 months Interval 8.44 to 14.32	14.6 months Interval 9.99 to 18.99

SECONDARY outcome

Timeframe: From randomization until death (up to approximately 42 months)

Population: ITT Population included all participants who were randomized.

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

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=227 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group	12.8 months Interval 10.84 to 14.78	16.1 months Interval 11.4 to 20.24

SECONDARY outcome

Timeframe: Up to Cycle 6 (up to approximately Day 168)

Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 post-baseline disease assessment. Number analyzed is the number of participants with data available for analysis for the specified category.

Responses for HR MDS/CMML are based on Modified International Working Group (IWG) Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR and PR for HR MDS/CMML and CR+CR with incomplete blood count recovery(CRi)+PR for low-blast AML. CR for HR MDS/CMML:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11g/dL hemoglobin (Hgb),\>=100\*10\^9/L platelet (pl),\>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood, and PR:all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still \>5%. For low-blast AML-CR:morphologic leukemia-free state,\>1.0\*10\^9 neutrophils, \>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L/thrombocytopenia (pl\<100\*10\^9/L); PR:all CR hematological values but\>=50% decrease in percentage of blasts to 5%-25% in bone marrow aspirate.

Outcome measures

Outcome measures
Measure	Azacitidine 75 mg/m^2 n=206 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 n=208 Participants Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles.
Number of Participants With Overall Response by Cycle 6 Overall Response for Low-blast AML	13 Participants	22 Participants
Number of Participants With Overall Response by Cycle 6 Overall Response for HR MDS/CMML	36 Participants	29 Participants

Adverse Events

Azacitidine 75 mg/m^2

Serious events: 145 serious events

Other events: 207 other events

Deaths: 153 deaths

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

Serious events: 156 serious events

Other events: 210 other events

Deaths: 150 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