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Clinical Trial Results:
A Phase 3, Randomized, Controlled, Open-label, Clinical Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia

Summary
EudraCT number	2017-000318-40
Trial protocol	GB DE CZ ES FR BE IT
Global end of trial date	14 Oct 2024

Results information
Results version number	v1(current)
This version publication date	26 Oct 2025
First version publication date	26 Oct 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

Pevonedistat-3001

ISRCTN number

US NCT number

NCT03268954

WHO universal trial number (UTN)

U1111-1189-8055

Sponsor organisation name

Takeda

Sponsor organisation address

95 Hayden Avenue, Lexington, MA, United States, 02421

Public contact

Study Director, Takeda, TrialDisclosures@takeda.com

Scientific contact

Study Director, Takeda, TrialDisclosures@takeda.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

14 Oct 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Oct 2024

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial was to determine whether the combination of pevonedistat and azacitidine improves event-free survival (EFS), when compared with single-agent azacitidine. (An event is defined as death or transformation to acute myeloid leukemia (AML) in participants with MDS or CMML, whichever occurs first, and is defined as death in participants with low-blast AML.)

Protection of trial subjects

Participant signed an informed consent form (ICF) before participating in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Nov 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

38 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

Belgium: 11

Country: Number of subjects enrolled

Brazil: 28

Country: Number of subjects enrolled

China: 2

Country: Number of subjects enrolled

Czechia: 16

Country: Number of subjects enrolled

Germany: 9

Country: Number of subjects enrolled

Spain: 49

Country: Number of subjects enrolled

France: 21

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

Greece: 58

Country: Number of subjects enrolled

Israel: 12

Country: Number of subjects enrolled

Italy: 23

Country: Number of subjects enrolled

Japan: 38

Country: Number of subjects enrolled

Korea, Republic of: 6

Country: Number of subjects enrolled

Poland: 21

Country: Number of subjects enrolled

Russian Federation: 34

Country: Number of subjects enrolled

Türkiye: 10

Country: Number of subjects enrolled

Canada: 9

Country: Number of subjects enrolled

Mexico: 7

Country: Number of subjects enrolled

United States: 89

Worldwide total number of subjects

454

EEA total number of subjects

208

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

383

85 years and over

Subject disposition

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Recruitment details

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

Screening details

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

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Azacitidine 75 mg/m^2

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for suspension for injection

Routes of administration

Subcutaneous use, Intravenous use

Dosage and administration details

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

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Pevonedistat

Investigational medicinal product code

TAK-924

Other name

MLN4924

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

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.

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for suspension for injection

Routes of administration

Subcutaneous use, Intravenous use

Dosage and administration details

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.

Number of subjects in period 1	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Started	227	227
Safety Population	220	223
Completed	195	199
Not completed	32	28
Consent withdrawn by subject	27	17
Reason Not Specified	3	8
Lost to follow-up	2	3

Baseline characteristics

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Reporting group title

Azacitidine 75 mg/m^2

Reporting group description

Reporting group title

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

Reporting group description

Reporting group values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	Total
Number of subjects	227	227
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	73.0 ( 8.22 )	73.0 ( 7.65 )	-
Gender categorical
Units: Subjects
Male	142	132	274
Female	85	95	180
Ethnicity
Units: Subjects
Hispanic or Latino	26	31	57
Not Hispanic or Latino	188	189	377
Unknown or Not Reported	13	7	20
Race
Units: Subjects
American Indian or Alaska Native	2	4	6
Asian	20	31	51
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	1	2	3
White	189	180	369
More than one race	0	0	0
Unknown or Not Reported	15	10	25
Region of Enrollment
Units: Subjects
Australia	3	4	7
Belgium	8	3	11
Brazil	10	18	28
China	2	0	2
Czech Republic	10	6	16
Germany	6	3	9
Spain	26	23	49
France	13	8	21
United Kingdom	1	3	4
Greece	30	28	58
Israel	6	6	12
Italy	14	9	23
Japan	12	26	38
Korea, Republic of	4	2	6
Poland	11	10	21
Russia	22	12	34
Turkey	5	5	10
Canada	2	7	9
Mexico	2	5	7
United States	40	49	89
Height
999 is a placeholder value for the data that is reported in other subject analysis set or arm group, due to difference in number of subjects analyzed.
Units: centimeter (cm)
arithmetic mean (standard deviation)	999 ( 999 )	999 ( 999 )	-
Weight
999 is a placeholder value for the data that is reported in other subject analysis set or arm group, due to difference in number of subjects analyzed.
Units: kilogram (kg)
arithmetic mean (standard deviation)	77.65 ( 16.143 )	999 ( 999 )	-
Body Surface Area
Body surface area is defined as [height (cm) × weight (kg) / 3600]^1/2. 999 is a placeholder value for the data that is reported in other subject analysis set or arm group, due to difference in number of subjects analyzed.
Units: meter square (m^2)
arithmetic mean (standard deviation)	999 ( 999 )	999 ( 999 )	-

Subject analysis set title

Azacitidine 75 mg/m^2

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

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

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

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

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis sets values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects	225	223	226
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	0 ( )	0 ( )	0 ( )
Gender categorical
Units: Subjects
Male	0	0	0
Female	0	0	0
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	0
Not Hispanic or Latino	0	0	0
Unknown or Not Reported	0	0	0
Race
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	0	0
White	0	0	0
More than one race	0	0	0
Unknown or Not Reported	0	0	0
Region of Enrollment
Units: Subjects
Australia	0	0	0
Belgium	0	0	0
Brazil	0	0	0
China	0	0	0
Czech Republic	0	0	0
Germany	0	0	0
Spain	0	0	0
France	0	0	0
United Kingdom	0	0	0
Greece	0	0	0
Israel	0	0	0
Italy	0	0	0
Japan	0	0	0
Korea, Republic of	0	0	0
Poland	0	0	0
Russia	0	0	0
Turkey	0	0	0
Canada	0	0	0
Mexico	0	0	0
United States	0	0	0
Height
999 is a placeholder value for the data that is reported in other subject analysis set or arm group, due to difference in number of subjects analyzed.
Units: centimeter (cm)
arithmetic mean (standard deviation)	167.59 ( 9.439 )	166.31 ( 10.098 )	999 ( 999 )
Weight
999 is a placeholder value for the data that is reported in other subject analysis set or arm group, due to difference in number of subjects analyzed.
Units: kilogram (kg)
arithmetic mean (standard deviation)	999 ( 999 )	999 ( 999 )	75.82 ( 15.996 )
Body Surface Area
Body surface area is defined as [height (cm) × weight (kg) / 3600]^1/2. 999 is a placeholder value for the data that is reported in other subject analysis set or arm group, due to difference in number of subjects analyzed.
Units: meter square (m^2)
arithmetic mean (standard deviation)	1.89 ( 0.228 )	1.86 ( 0.233 )	999 ( 999 )

End points

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Reporting group title

Azacitidine 75 mg/m^2

Reporting group description

Reporting group title

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

Reporting group description

Subject analysis set title

Azacitidine 75 mg/m^2

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

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

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

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

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Primary: Event-Free Survival (EFS)

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End point title

Event-Free Survival (EFS)

End point description

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. Intent-to-Treat (ITT) population included all participants who were randomized.

End point type

Primary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	227	227
Units: months
median (confidence interval 95%)	15.7 (14.42 to 19.68)	17.7 (13.63 to 20.24)

Event-Free Survival (EFS)

Comparison groups

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

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.557 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.968

Confidence interval

level

95%

sides

2-sided

lower limit

0.757

upper limit

1.238

Notes
[1] - HR:unadjusted stratified Cox proportional hazard regression with stratification(low-blast AML,Revised International Prognostic Scoring System (IPSS-R) risk groups=very high,high,or intermediate for higher-risk (HR)MDS/CMML),treatment as factor.HR<1:better prevention of EFS in combination arm than azacitidine arm.
[2] - P-value comparing EFS between treatment groups was based on the 1-sided Cui-Hung-Wang weighted unstratified log-rank test.

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Overall survival was defined as the time from randomization to death from any cause. ITT Population included all participants who were randomized.

End point type

Secondary

End point timeframe

Up to approximately 6.9 years

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	227	227
Units: months
median (confidence interval 95%)	16.8 (14.92 to 20.11)	20.3 (17.97 to 22.60)

Overall Survival (OS)

Comparison groups

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

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.152 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.888

Confidence interval

level

95%

sides

2-sided

lower limit

0.709

upper limit

1.113

Notes
[3] - HR:unadjusted stratified Cox proportional hazard regression with stratification(low-blast AML,IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR<1: longer survival time in combination arm than azacitidine arm.
[4] - P-value comparing OS between treatment groups was based on the 1-sided Cui-Hung-Wang weighted unstratified log-rank test.

Secondary: Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60

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End point title

Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60

End point description

60-day mortality was defined as number of participants who died within 60 days from the first dose of study drug. Safety Population included all enrolled participants who received at least 1 dose of azacitidine alone or pevonedistat + azacitidine.

End point type

Secondary

End point timeframe

Up to Day 60

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	220	223
Units: participants	15	14

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimates of Six-Month Survival Rate

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End point title

Kaplan-Meier Estimates of Six-Month Survival Rate

End point description

Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of Month 6 from randomization are presented. ITT Population included all participants who were randomized. Subjects analysed is the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

Month 6

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	174	174
Units: percentage probability
number (confidence interval 95%)	0.825 (0.767 to 0.869)	0.810 (0.752 to 0.856)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimates of One-Year Survival Rate

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End point title

Kaplan-Meier Estimates of One-Year Survival Rate

End point description

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. ITT Population included all participants who were randomized. Subjects analysed is the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

Year 1

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	141	137
Units: percentage probability
number (confidence interval 95%)	0.693 (0.626 to 0.751)	0.646 (0.578 to 0.706)

No statistical analyses for this end point

Secondary: Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30

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End point title

Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30

End point description

30-day mortality was defined as number of participants who died within 30 days from the first dose of study drug. Safety Population included all enrolled participants who received at least 1 dose of azacitidine alone or pevonedistat + azacitidine.

End point type

Secondary

End point timeframe

Up to Day 30

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	220	223
Units: participants	6	5

No statistical analyses for this end point

Secondary: 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

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End point title

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

End point description

Time to AML transformation in HR MDS & CMML participants: time from randomization to documented AML transformation as determined by 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 blood or marrow & increase of blast count by 50%.ITT Population=all randomized participants. Subjects analysed: number (no.) of participants with data available for analyses. 'n'=no. of participants with data available for analysis for given category. 999 indicates median, lower and/or upper limit (UL) of 95% confidence interval (CI) not estimable due to low no. of participants with event.

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	174	177
Units: months
median (confidence interval 95%)
HR MDS Participants (n=163,161)	35.6 (26.51 to 999)	999 (23.29 to 999)
HR CMML Participants (n=11,16)	999 (999 to 999)	999 (999 to 999)
HR MDS/CMML Participants (n=174,177)	35.6 (29.04 to 999)	999 (24.28 to 999)

Time to AML Transformation in HR MDS Participants

Comparison groups

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

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.562 ^[6]

Method

Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.037

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

1.63

Notes
[5] - HR:unadjusted stratified Cox proportional HazardRegression with stratification(IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR<1:better prevention of AML transformation in combination arm than azacitidine arm.
[6] - P-value comparing time to AML Transformation between treatment groups was based on 1-sided stratified log-rank test stratified by IPSS-R risk groups of very high, high, or intermediate for HR MDS.

Time to AMLTransformation:HR MDS/CMML Participants

Comparison groups

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

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.558 ^[8]

Method

Log Rank

Parameter type

Hazard ratio (HR)

Point estimate

1.034

Confidence interval

level

95%

sides

2-sided

lower limit

0.663

upper limit

1.61

Notes
[7] - HR:unadjusted stratified Cox proportional HazardRegression with stratification(IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR<1:better prevention of AML transformation in combination arm than azacitidine arm.
[8] - P-value comparing time to AML Transformation between treatment groups was based on 1-sided stratified log-rank test stratified by IPSS-R risk groups of very high, high, or intermediate for HR CMML/MDS.

Time to AML Transformation in HR CMML Participants

Comparison groups

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

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.603 ^[10]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.512

Confidence interval

level

95%

sides

2-sided

lower limit

0.068

upper limit

33.773

Notes
[9] - HR:unadjusted stratified Cox proportional HazardRegression with stratification(IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR<1:better prevention of AML transformation in combination arm than azacitidine arm.
[10] - P-value comparing time to AML Transformation between treatment groups was based on 1-sided stratified log-rank test stratified by IPSS-R risk groups of very high, high, or intermediate for HR CMML.

Secondary: Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi)

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End point title

Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi)

End point description

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). 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.

End point type

Secondary

End point timeframe

From randomization until CR (up to approximately 42 months)

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	206	208
Units: participants	71	63

Complete Remission (CR) and CR+ Complete Remission

Statistical analysis description

Number of Participants With Complete Remission (CR) and CR+Complete Remission with Incomplete Blood Count Recovery (CRi)

Comparison groups

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

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.374 ^[11]

Method

Cochran-Mantel-Haenszel

Parameter type

Absolute Rate Difference

Point estimate

-4.18

Confidence interval

level

95%

sides

2-sided

lower limit

-13.18

upper limit

4.83

Notes
[11] - P-value was obtained from a stratified Cochran-Mantel-Haenszel chi-square test stratified by low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Secondary: Number of Participants With CR and Marrow CR

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End point title

Number of Participants With CR and Marrow CR

End point description

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

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	206	208
Units: participants	91	87

No statistical analyses for this end point

Secondary: Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI)

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End point title

Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI)

End point description

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

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	206	208
Units: participants	77	76

No statistical analyses for this end point

Secondary: Number of Participants With CR and Marrow CR and PR

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End point title

Number of Participants With CR and Marrow CR and PR

End point description

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	206	208
Units: participants	91	87

No statistical analyses for this end point

Secondary: Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI)

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End point title

Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI)

End point description

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

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	206	208
Units: participants	112	117

No statistical analyses for this end point

Secondary: Number of Participants With Overall Response (OR)

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End point title

Number of Participants With Overall Response (OR)

End point description

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

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	206	208
Units: participants	73	64

Number of Participants with OR

Comparison groups

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

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.329 ^[12]

Method

Cochran-Mantel-Haenszel

Parameter type

Absolute Rate Difference

Point estimate

-4.67

Confidence interval

level

95%

sides

2-sided

lower limit

-13.72

upper limit

4.39

Notes
[12] - P-value was obtained from a stratified Cochran-Mantel-Haenszel chi-square test stratified by low-blast AML, Revised International Prognostic Scoring System (IPSS-R) risk groups of very high, high, or intermediate for HR MDS/CMML.

Secondary: Number of Participants With Overall Response 2 (OR2)

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End point title

Number of Participants With Overall Response 2 (OR2)

End point description

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(NL),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 & by 100%;NL 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 NL,≥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.No. of responders determined by independent review committee(IRC).REP.Data is reported for responders.3 participants not counted as responders for OR2 as IRC assessed these participants as non-responders.

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	206	208
Units: participants	94	94

Number of Participants with OR2

Comparison groups

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

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.891 ^[13]

Method

Cochran-Mantel-Haenszel

Parameter type

Absolute Rate Difference

Point estimate

-0.44

Confidence interval

level

95%

sides

2-sided

lower limit

-10.03

upper limit

9.15

Notes
[13] - P-value was obtained from a stratified Cochran-Mantel-Haenszel chi-square test stratified by low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Secondary: Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi)

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End point title

Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi)

End point description

Duration of CR is 1st documented CR to 1st documentation of PD or relapse from CR (participants with low-blast AML). Disease responses for low-blast AML were based on Revised IWG Response Criteria for AML. CR:≤5% myeloblasts with normal maturation of all cell lines in bone marrow, & ≥11g/dL Hgb, ≥100*10^9/liter(/L) pl, ≥1.0*10^9/L neutrophils & 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 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 criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (pl<100*10^9/L). REP included all participants who received at least 1 dose of study drug & had a Baseline & at least 1 postbaseline disease assessment. Data is reported for participants with CR & CRi. 999: upper limit of 95% CI was not estimable due to low no. of participants with event.

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	15	17
Units: months
median (confidence interval 95%)	8.5 (3.02 to 999)	15.0 (3.94 to 999)

Duration

Statistical analysis description

Duration of Complete Remission + Complete Remission with Incomplete Blood Count Recovery (CRi)

Comparison groups

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

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.373 ^[15]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.846

Confidence interval

level

95%

sides

2-sided

lower limit

0.306

upper limit

2.339

Notes
[14] - Hazard ratio was based on an unadjusted unstratified Cox proportional hazard regression model with treatment as a factor in the model.
[15] - P-value comparing duration of CR+CRi between treatment groups was based on 1-sided unstratified log-rank.

Secondary: Duration of Complete Remission (CR)

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End point title

Duration of Complete Remission (CR)

End point description

Duration of CR is 1st documented CR to 1st documentation of PD/relapse from CR(participants with low-blast AML)/relapse after CR/PR(participants with HR MDS/CMML).Disease responses for HR MDS/CMML are based on Modified IWG Response Criteria for MDS & 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/dLHgb,≥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 more than 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 criteria for CR except for residual neutropenia(<1.0*10^9/L) or thrombocytopenia(pl<100*10^9/L).REP.Data is reported for participants with complete remission.999:UL of 95% CI was not estimable due to low no. of participants with event.

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	68	57
Units: months
median (confidence interval 95%)	13.1 (6.93 to 29.08)	17.2 (13.96 to 999)

Duration of CR

Comparison groups

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

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

superiority ^[16]

P-value

= 0.072 ^[17]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.679

Confidence interval

level

95%

sides

2-sided

lower limit

0.402

upper limit

1.146

Notes
[16] - Hazard ratio was based on an unadjusted stratified Cox proportional hazard regression model with stratification factors (low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML) and treatment as a factor in the model.
[17] - P-value was based on 1-sided log-rank test stratified by low-blast AML,IPSS-R risk groups of very high,high,or intermediate for HR MDS/CMML.

Secondary: Duration of Overall Response (OR)

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End point title

Duration of Overall Response (OR)

End point description

Duration of OR:response to 1st 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 & CR+Cri+PR for low-blast AML.CR for HR MDS/CMML:≤5% myeloblasts with normal maturation of all BM cell lines,≥11 g/dL Hgb,≥100*10^9/L pl,≥1.0*10^9/L NL,0% blasts in peripheral blood &PR:all CR criteria met except BM blasts≥50% decrease over pretreatment but still>5%.For low-blast AML-CR:morphologic leukemia-free state>1.0*10^9 NL,≥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 BM aspirate.REP.Responders were analyzed.999:upper limit of 95% CI not estimable due to fewer subjects with event.

End point type

Secondary

End point timeframe

Up to approximately 42 months

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	73	64
Units: months
median (confidence interval 95%)	18.3 (8.31 to 999)	17.1 (12.68 to 999)

Duration of Overall Response (OR)

Comparison groups

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

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.32 ^[19]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.889

Confidence interval

level

95%

sides

2-sided

lower limit

0.542

upper limit

1.458

Notes
[18] - Hazard ratio was based on an unadjusted stratified Cox proportional hazard regression model with stratification factors (low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML) and treatment as a factor in the model.
[19] - P-value comparing duration of PR or better response between treatment groups was based on 1-sided log-rank test stratified by low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Secondary: Duration of Overall Response 2 (OR2)

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End point title

Duration of Overall Response 2 (OR2)

End point description

Duration of OR2:1st documentation of CR+PR+HI to 1st documentation of PD/relapse after CR/PR for responders(CR+PR+HI=HR MDS/CMML;CR,CRi,PR=low-blast AML).For HR MDS/CMML-CR:≤5%myeloblasts+normal maturation of all BM cell lines,≥11g/dL Hgb,≥100*10^9/L pl,≥1.0*10^9/L NL,0%peripheral blood blasts;PR:CR criteria except BMblasts≥50%decrease(pretreatment),still>5%;HI:Hgb inc≥1.5g/dL if BL<11g/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 by ≥100%;NL100% inc &absolute >0.5*10^9/L inc if BL<1.0*10^9/L.For low-blast AML-CR:morphologic leukemia-free state,>1.0*10^9 NL,≥100*10^9/L pl,transfusion independence,no residual evidence of extramedullary leukemia;CRi:CR criteria except residual neutropenia<1.0*10^9/L or pl<100*10^9/L;PR:CR hematological values but≥50%decrease in BM aspirate.REP.As duration of OR2 could be derived based on criteria for HR MDS/CMML subjects,3 non-responders(per IRC)included in analysis.999:95%CI(UL)not estimable due to fewer subjects with event.

End point type

Secondary

End point timeframe

Up to approximately 42 months

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	95	96
Units: months
median (confidence interval 95%)	18.3 (11.17 to 30.92)	18.9 (15.01 to 999)

Duration of Overall Response 2 (OR2)

Comparison groups

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

Number of subjects included in analysis

191

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.151 ^[21]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.796

Confidence interval

level

95%

sides

2-sided

lower limit

0.514

upper limit

1.231

Notes
[20] - Hazard ratio was based on an unadjusted stratified Cox proportional hazard regression model with stratification factors (low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML) and treatment as a factor in the model.
[21] - P-value comparing duration of overall response 2 between treatment groups was based on 1-sided log-rank test stratified by low blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Secondary: Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence

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End point title

Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence

End point description

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. ITT Population included all participants who were randomized. Subjects analyzed is the number of participants from a subset of the ITT Population who were transfusion dependent at Baseline. 'n' is the number of participants who were transfusion dependent at Baseline for the specified category.

End point type

Secondary

End point timeframe

Up to approximately 42 months

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	140	129
Units: percentage of participants
number (not applicable)
RBCs-transfusion Independence (n=131,122)	44.3	47.5
Platelet-transfusion Independence (n=45,33)	48.9	45.5

Platelet-transfusion Independence

Comparison groups

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

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.477 ^[22]

Method

Cochran-Mantel-Haenszel

Parameter type

Absolute Rate Difference

Point estimate

-3.43

Confidence interval

level

95%

sides

2-sided

lower limit

-25.84

upper limit

18.97

Notes
[22] - P-value was obtained from a stratified Cochran-Mantel-Haenszel chi-square test.

RBC-transfusion Independence

Comparison groups

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

Number of subjects included in analysis

269

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.573 ^[23]

Method

Cochran-Mantel-Haenszel

Parameter type

Absolute Rate Difference

Point estimate

3.27

Confidence interval

level

95%

sides

2-sided

lower limit

-9.02

upper limit

15.55

Notes
[23] - P-value was obtained from a stratified Cochran-Mantel-Haenszel chi-square test.

Secondary: Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence

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End point title

Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence

End point description

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

End point type

Secondary

End point timeframe

Up to approximately 42 months

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	227	227
Units: months
median (confidence interval 95%)
RBC Transfusion Independence(n=58,58)	15.6 (10.18 to 28.09)	13.5 (9.07 to 16.66)
Platelet Transfusion Independence (n=22,15)	14.9 (5.09 to 23.23)	11.6 (2.73 to 16.26)
Transfusion Independence (n=63,59)	12.0 (8.90 to 19.48)	13.5 (10.38 to 16.66)

Duration of RBC Transfusion Independence

Comparison groups

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

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

P-value

= 0.774 ^[25]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.231

Confidence interval

level

95%

sides

2-sided

lower limit

0.715

upper limit

2.119

Notes
[24] - HR:unadjusted Cox Proportional Hazard regression;stratification(low-blast AML,IPSS-R risk groups=very high,high,intermediate for HRMDS/CMML),treatment as factor.HR<1:longer duration of transfusion independence in combination arm than azacitidine arm.
[25] - P-value comparing duration of RBC or platelet transfusion between treatment groups was based on 1-sided log-rank test stratified by low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Duration of Platelet Transfusion Independence

Comparison groups

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

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.801 ^[27]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.533

Confidence interval

level

95%

sides

2-sided

lower limit

0.567

upper limit

4.147

Notes
[26] - HR:unadjusted Cox Proportional Hazard regression;stratification(low-blast AML,IPSS-R risk groups=very high,high,intermediate for HRMDS/CMML),treatment as factor.HR<1:longer duration of transfusion independence in combination arm than azacitidine arm.
[27] - P-value comparing duration of platelet transfusion between treatment groups was based on 1-sided log-rank test stratified by low blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Duration of Transfusion Independence

Comparison groups

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

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.45 ^[29]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.968

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

1.614

Notes
[28] - HR:unadjusted Cox Proportional Hazard regression;stratification(low-blast AML,IPSS-R risk groups=very high,high,intermediate for HRMDS/CMML),treatment as factor.HR<1:longer duration of transfusion independence in combination arm than azacitidine arm.
[29] - P-value comparing duration of RBC or platelet transfusion between treatment groups was based on 1-sided log-rank test stratified by low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Secondary: Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi)

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End point title

Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi)

End point description

Time to 1st CR/PR:time from randomization to 1st documented CR/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 & for low-blast AML on Revised IWG Response Criteria for AML.For HR MDS or CMML-CR:≤5% myeloblasts with normal maturation of all BM cell lines,≥11 g/dL Hgb,≥100*10^9/L pl,≥1.0*10^9/L NL,0% blasts in peripheral blood;PR: all CR criteria met except BM blasts≥50% decrease over pretreatment but still>5%;For low-blast AML-CR:morphologic leukemia-free state,>1.0*10^9/L NL, 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 ≥50% in % of blasts to 5% to 25% in BM aspirate.REP.999:median, & upper limit of 95% CI was not estimable due to low no. of participants with event.

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	206	208
Units: months
median (confidence interval 95%)	999 (12.12 to 999)	999 (24.61 to 999)

Time to 1st CR/PR/Cr With Incomplete Blood CRi

Comparison groups

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

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

= 0.228 ^[31]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.628

upper limit

1.234

Notes
[30] - Hazard ratio was based on an unadjusted stratified Cox proportional hazard regression model with stratification factors (low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML) and treatment as a factor in the model.
[31] - P-value comparing time to first CR or PR or CRi (low-blast AML) between treatment groups was based on 1-sided stratified log-rank test stratified by low-blast AML,IPSS-R risk groups of very high,high,or intermediate for HR MDS/CMML.

Secondary: Number of Participants With Hematologic Improvement (HI)

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End point title

Number of Participants With Hematologic Improvement (HI)

End point description

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. REP included all participants who received at least 1 dose of study drug and had a baseline and at least 1 postbaseline disease assessment. Subjects analysed is the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

From randomization until HI (up to approximately 42 months)

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	157	163
Units: participants	76	70

Number of Participants With HI

Comparison groups

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

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.32 ^[32]

Method

Cochran-Mantel-Haenszel

Parameter type

Absolute Rate Difference

Point estimate

-5.46

Confidence interval

level

95%

sides

2-sided

lower limit

-16.36

upper limit

5.44

Notes
[32] - P-value was obtained from a stratified Cochran-Mantel-Haenszel chi-square test.

Secondary: Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML

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End point title

Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML

End point description

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%. ITT Population included all participants who were randomized.

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	227	227
Units: participants	3	9

Inpatient Hospital Admissions

Statistical analysis description

Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML

Comparison groups

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

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Rate Difference

Point estimate

2.64

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

5.58

Secondary: Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death

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End point title

Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death

End point description

Time to PD,relapse after CR(low-blast AML),relapse after CR/PR(HR MDS/CMML),or death,defined as time from date of randomization until date of 1st documentation of PD,relapse after CR(low-blast AML),relapse after CR/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,with20%-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.ITT Population.

End point type

Secondary

End point 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)

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	227	227
Units: months
median (confidence interval 95%)	11.8 (10.25 to 13.31)	13.1 (11.01 to 15.84)

Statistical Analysis 1

Statistical analysis description

Time to Progressive Disease (PD), Relapse after CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death

Comparison groups

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

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.084 ^[34]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.858

Confidence interval

level

95%

sides

2-sided

lower limit

0.689

upper limit

1.067

Notes
[33] - Hazard ratio was based on a stratified Cox proportional hazard regression model stratified by low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML, with treatment as a factor in the model.
[34] - P-value was obtained from a stratified 1-sided log-rank test stratified by low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Secondary: 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

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End point title

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

End point description

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(GHS)/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. ITT Population included all participants who were randomised. All participants with PRO measurements at baseline and with data available at end of treatment were analysed for this endpoint.

End point type

Secondary

End point timeframe

Baseline, at approximately 58 months

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	211	210
Units: score on a scale
arithmetic mean (standard deviation)
GHS/QoL Score: BL (n=211,210)	60.3 ( 22.11 )	61.6 ( 21.13 )
GHS/QoL Score: Change from BL (n=146,124)	-3.0 ( 25.93 )	-8.4 ( 26.89 )
Physical Functioning (PF) Score: BL(n=211,210)	69.4 ( 22.63 )	75.7 ( 20.38 )
PF Score: Change from BL (n=146,125)	-7.5 ( 22.82 )	-13.4 ( 27.51 )
Role Functioning (RF) Score: BL (n=211,210)	66.9 ( 30.88 )	73.7 ( 28.55 )
RF Score: Change from BL(n=146,126)	-11.8 ( 35.41 )	-18.3 ( 36.72 )
Emotional Functioning (EF) Score: BL (n=211,210)	76.0 ( 20.96 )	77.6 ( 22.10 )
EF Score: Change from BL(n=146,124)	-2.5 ( 23.80 )	-5.9 ( 22.41 )
Cognitive Functioning (CF) Score: BL (n=211,210)	84.6 ( 18.29 )	86.1 ( 17.60 )
CF Score: Change from BL (n=146,125)	-7.2 ( 22.65 )	-10.4 ( 24.38 )
Social Functioning (SF) Score: BL (n=211,208)	79.3 ( 25.37 )	78.8 ( 25.82 )
SF Score: Change from BL (n=146,122)	-13.7 ( 33.89 )	-16.5 ( 34.78 )
Fatigue Score: BL (n=211,210)	38.5 ( 25.44 )	33.8 ( 24.24 )
Fatigue Score: Change from BL (n=146,126)	6.6 ( 26.41 )	12.3 ( 31.22 )
Nausea/Vomiting Score: BL (n=211,210)	4.6 ( 11.39 )	4.7 ( 10.96 )
Nausea/Vomiting Score:Change from BL(n=146,125)	2.4 ( 19.08 )	1.9 ( 15.00 )
Pain Score: BL (n=211,210)	20.9 ( 25.55 )	19.4 ( 26.42 )
Pain Score: Change from BL (n=146,125)	5.8 ( 30.36 )	6.8 ( 33.34 )
Dyspnoea Score: BL (n=211,210)	25.4 ( 29.83 )	24.4 ( 28.90 )
Dyspnoea Score:Change from BL(n=146,124)	5.9 ( 28.95 )	5.9 ( 29.46 )
Insomnia Score: BL (n=211,210)	27.2 ( 27.96 )	25.7 ( 30.68 )
Insomnia Score: Change from BL (n=145,124)	3.2 ( 34.32 )	4.6 ( 34.09 )
Appetite Loss Score: BL (n=211,210)	23.4 ( 29.29 )	15.6 ( 23.99 )
Appetite Loss Score: Change from BL (n=146,125)	4.6 ( 38.68 )	16.0 ( 34.03 )
Constipation Score: BL (n=211,210)	14.7 ( 24.78 )	13.8 ( 22.47 )
Constipation Score:Change from BL(n=146,125)	5.5 ( 29.56 )	5.1 ( 28.42 )
Diarrhoea Score: BL (n=211,210)	7.6 ( 18.84 )	7.0 ( 16.75 )
Diarrhoea Score: Change from BL (n=146,124)	3.0 ( 22.80 )	1.9 ( 27.65 )
Financial Difficulties (FD) Score: BL (n=211,208)	14.2 ( 25.37 )	18.4 ( 26.76 )
FD Score: Change from BL (n=146,122)	5.9 ( 27.03 )	7.4 ( 30.46 )
QLQ-C30 Summary Score: BL (n=211,208)	77.9 ( 14.90 )	80.5 ( 15.08 )
QLQ-C30 Summary Score:Change from BL (n=145,120)	-6.1 ( 18.84 )	-8.6 ( 17.75 )

No statistical analyses for this end point

Secondary: Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

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End point title

Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

End point description

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. ITT Population included all participants who were randomized.

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	227	227
Units: months
median (confidence interval 95%)	12.8 (8.44 to 14.32)	14.6 (9.99 to 18.99)

Event-Free Surviva

Statistical analysis description

Event-Free Survival in Participants who have TP53 Mutations, 17p Deletions, and/or are Determined to be in an Adverse Cytogenetic Risk Group

Comparison groups

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

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

= 0.24 ^[36]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.877

Confidence interval

level

95%

sides

2-sided

lower limit

0.608

upper limit

1.263

Notes
[35] - HR:unadjusted stratified Cox proportional hazard regression with stratification factors (IPSS-R risk groups=very high,high,or intermediate for HRMDS/CMML),treatment as factor.HR<1:better prevention of EFS in combination arm than azacitidine arm.
[36] - P-value comparing EFS between treatment groups was based on 1-sided log-rank test stratified by low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Secondary: 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

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End point title

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

End point description

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 & CR+CRi+PR for low-blast AML.CR for HR MDS/CMML:≤5% myeloblasts with normal maturation of all BM cell lines,≥11 g/dL Hgb,≥100*10^9/L pl,≥1.0*10^9/L NL,0% blasts in peripheral blood and PR:all CR criteria met except BM blasts≥50% decrease over pretreatment but still>5%.For low-blast AML-CR:morphologic leukemia-free state,>1.0*10^9 NL,≥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.ITT Population.Subjects analysed:participants with data available for analyses.'n':participants with data available for analysis for specified category.

End point type

Secondary

End point timeframe

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

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	52	54
Units: participants
OR: HR MDS/CMML Participants (n=52,54)	14	13
OR: Low-blast AML Participants (n=37,32)	13	12

ORR: Low-blast AML Participants

Comparison groups

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

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.84 ^[37]

Method

Cochran-Mantel-Haenszel

Parameter type

Absolute Rate Difference

Point estimate

2.36

Confidence interval

level

95%

sides

2-sided

lower limit

-20.39

upper limit

25.12

Notes
[37] - P-value for Low-blast AML was obtained from an unstratified Cochran-Mantel-Haenszel chi-square test.

OR: HR MDS/CMML Participants

Comparison groups

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

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.683 ^[38]

Method

Cochran-Mantel-Haenszel

Parameter type

Absolute Rate Difference

Point estimate

-2.85

Confidence interval

level

95%

sides

2-sided

lower limit

-19.44

upper limit

13.75

Notes
[38] - P-value for HR MDS/CMML was obtained from a stratified Cochran-Mantel-Haenszel chi-square test

Secondary: Number of Participants With Overall Response by Cycle 6

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End point title

Number of Participants With Overall Response by Cycle 6

End point description

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 & PR for HR MDS/CMML & CR+CR with CRi+PR for low-blast AML.CR for HR MDS/CMML:≤5% myeloblasts with normal maturation of all bone marrow cell lines,≥11g/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;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.REP used.'n' is the no. of participants with data available for analysis for the specified category.

End point type

Secondary

End point timeframe

Up to Cycle 6 (up to approximately Day 168)

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	206	208
Units: participants
Overall Response for HR MDS/CMML (n=157,163)	36	29
Overall Response for Low-blast AML (n=49,45)	13	22

Overall Response for HR MDS/CMML

Comparison groups

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

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.261 ^[39]

Method

Cochran-Mantel-Haenszel

Parameter type

Absolute Rate Difference

Point estimate

-5.14

Confidence interval

level

95%

sides

2-sided

lower limit

-13.95

upper limit

3.68

Notes
[39] - P-value was obtained from a stratified Cochran-Mantel-Haenszel chi-square test stratified by IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Overall Response for Low-blast AML

Comparison groups

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

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026 ^[40]

Method

Cochran-Mantel-Haenszel

Parameter type

Absolute Rate Difference

Point estimate

22.36

Confidence interval

level

95%

sides

2-sided

lower limit

3.22

upper limit

41.49

Notes
[40] - P-value was obtained from an unstratified Cochran-Mantel-Haenszel chi-square test.

Secondary: Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

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End point title

Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

End point description

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. ITT Population included all participants who were randomized.

End point type

Secondary

End point timeframe

From randomization until death (up to approximately 42 months)

End point values	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Number of subjects analysed	227	227
Units: months
median (confidence interval 95%)	12.8 (10.84 to 14.78)	16.1 (11.40 to 20.24)

Overall Survival in Participants

Statistical analysis description

Overall Survival in Participants who have TP53 Mutations, 17p Deletions, and/or are Determined to be in an Adverse Cytogenetic Risk Group

Comparison groups

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

Number of subjects included in analysis

454

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

= 0.145 ^[42]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.826

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

1.178

Notes
[41] - HR:unadjusted stratified Cox proportional hazard regression with stratification factors(IPSS-R risk groups of very high,high,intermediate) and treatment as factor in model.HR<1: longer survival time in combination arm than azacitidine arm.
[42] - P-value comparing OS between treatment groups was based on 1-sided log-rank test stratified by low-blast AML, IPSS-R risk groups of very high, high, or intermediate for HR MDS/CMML.

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug up to end of study (up to approximately 6.9 years)

Adverse event reporting additional description

The Safety Population included all participants who received at least 1 dose of study drug (i.e., pevonedistat + azacitidine or single-agent azacitidine).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

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

Reporting group description

Reporting group title

Azacitidine 75 mg/m^2

Reporting group description

Serious adverse events	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	Azacitidine 75 mg/m^2
Total subjects affected by serious adverse events
subjects affected / exposed	156 / 223 (69.96%)	145 / 220 (65.91%)
number of deaths (all causes)	150	153
number of deaths resulting from adverse events	42	36
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	3 / 223 (1.35%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 2
Adenocarcinoma of colon
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 223 (0.00%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Myelodysplastic syndrome
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Shock haemorrhagic
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	6 / 223 (2.69%)	16 / 220 (7.27%)
occurrences causally related to treatment / all	0 / 6	5 / 18
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Visceral pain
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Asthenia
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 223 (0.45%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2
Fatigue
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	2 / 223 (0.90%)	3 / 220 (1.36%)
occurrences causally related to treatment / all	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 223 (0.45%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Medical device site inflammation
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 223 (0.45%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2
Respiratory, thoracic and mediastinal disorders
Organising pneumonia
subjects affected / exposed	0 / 223 (0.00%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Acute pulmonary oedema
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Acute respiratory distress syndrome
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 223 (0.00%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Bronchiectasis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Dyspnoea
subjects affected / exposed	1 / 223 (0.45%)	3 / 220 (1.36%)
occurrences causally related to treatment / all	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hydrothorax
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngeal stenosis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 223 (0.45%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	3 / 223 (1.35%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary congestion
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 223 (0.90%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	2 / 223 (0.90%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 223 (0.45%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Product contamination microbial
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
C-reactive protein increased
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Occult blood
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count increased
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	2 / 223 (0.90%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Central nervous system injury
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 223 (0.00%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyphaema
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Refractoriness to platelet transfusion
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Poisoning
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Procedural haemorrhage
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue injury
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Thermal burn
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic haemorrhage
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Silent myocardial infarction
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 223 (0.45%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiovascular insufficiency
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiopulmonary failure
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	6 / 223 (2.69%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 6	0 / 1
Cardiac failure congestive
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	2 / 223 (0.90%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 1
Cardiac failure
subjects affected / exposed	3 / 223 (1.35%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	1 / 5	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2
Atrioventricular block complete
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral ischaemia
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Altered state of consciousness
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Central nervous system haemorrhage
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 223 (0.45%)	3 / 220 (1.36%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Dementia with Lewy bodies
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 223 (0.00%)	3 / 220 (1.36%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intracranial haematoma
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Haemorrhagic stroke
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Paraparesis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Syncope
subjects affected / exposed	3 / 223 (1.35%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	13 / 223 (5.83%)	10 / 220 (4.55%)
occurrences causally related to treatment / all	10 / 17	18 / 31
deaths causally related to treatment / all	0 / 0	0 / 0
Blood loss anaemia
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukostasis syndrome
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Leukocytosis
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	43 / 223 (19.28%)	35 / 220 (15.91%)
occurrences causally related to treatment / all	37 / 74	30 / 52
deaths causally related to treatment / all	0 / 0	1 / 1
Splenic infarction
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	10 / 223 (4.48%)	4 / 220 (1.82%)
occurrences causally related to treatment / all	15 / 15	5 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenic purpura
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	6 / 223 (2.69%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	5 / 8	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pure white cell aplasia
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness unilateral
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Glaucoma
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Conjunctival haemorrhage
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cataract
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vitreous haemorrhage
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gingival bleeding
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal vascular malformation haemorrhagic
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 223 (0.90%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal angiodysplasia
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric disorder
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	4 / 223 (1.79%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Proctalgia
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 223 (0.00%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal haemorrhage
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal ulcer haemorrhage
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Purpura
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal impairment
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Haematuria
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polypoid cystitis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Spondylitis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest wall haematoma
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	3 / 223 (1.35%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue necrosis
subjects affected / exposed	0 / 223 (0.00%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	1 / 1
Arthralgia
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal sepsis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Bacteraemia
subjects affected / exposed	2 / 223 (0.90%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Device related sepsis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	1 / 223 (0.45%)	5 / 220 (2.27%)
occurrences causally related to treatment / all	0 / 2	0 / 8
deaths causally related to treatment / all	0 / 1	0 / 3
Cellulitis
subjects affected / exposed	9 / 223 (4.04%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	1 / 9	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis staphylococcal
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colonic abscess
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19
subjects affected / exposed	1 / 223 (0.45%)	3 / 220 (1.36%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 223 (0.45%)	5 / 220 (2.27%)
occurrences causally related to treatment / all	0 / 1	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 1
Herpes zoster
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cyst infection
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Listeriosis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	5 / 223 (2.24%)	6 / 220 (2.73%)
occurrences causally related to treatment / all	0 / 7	0 / 7
deaths causally related to treatment / all	0 / 1	0 / 1
Lower respiratory tract infection fungal
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mucormycosis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	33 / 223 (14.80%)	25 / 220 (11.36%)
occurrences causally related to treatment / all	10 / 37	8 / 29
deaths causally related to treatment / all	1 / 4	0 / 1
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Perichondritis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paronychia
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	2 / 223 (0.90%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia legionella
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia pseudomonal
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonal bacteraemia
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Rectal abscess
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	3 / 223 (1.35%)	4 / 220 (1.82%)
occurrences causally related to treatment / all	0 / 3	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	6 / 223 (2.69%)	10 / 220 (4.55%)
occurrences causally related to treatment / all	5 / 9	0 / 13
deaths causally related to treatment / all	0 / 2	0 / 3
Septic shock
subjects affected / exposed	11 / 223 (4.93%)	6 / 220 (2.73%)
occurrences causally related to treatment / all	4 / 13	1 / 8
deaths causally related to treatment / all	3 / 8	0 / 4
Serratia bacteraemia
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin infection
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis septic
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	2 / 223 (0.90%)	5 / 220 (2.27%)
occurrences causally related to treatment / all	1 / 2	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	7 / 223 (3.14%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 8	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vulvitis
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	1 / 223 (0.45%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperferritinaemia
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	0 / 223 (0.00%)	2 / 220 (0.91%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	2 / 223 (0.90%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 223 (0.45%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	0 / 223 (0.00%)	1 / 220 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	Azacitidine 75 mg/m^2
Total subjects affected by non serious adverse events
subjects affected / exposed	210 / 223 (94.17%)	207 / 220 (94.09%)
Vascular disorders
Hypotension
subjects affected / exposed	13 / 223 (5.83%)	12 / 220 (5.45%)
occurrences all number	14	13
Hypertension
subjects affected / exposed	20 / 223 (8.97%)	14 / 220 (6.36%)
occurrences all number	20	21
General disorders and administration site conditions
Asthenia
subjects affected / exposed	34 / 223 (15.25%)	42 / 220 (19.09%)
occurrences all number	66	61
Pyrexia
subjects affected / exposed	53 / 223 (23.77%)	56 / 220 (25.45%)
occurrences all number	80	79
Oedema peripheral
subjects affected / exposed	29 / 223 (13.00%)	30 / 220 (13.64%)
occurrences all number	41	58
Injection site pain
subjects affected / exposed	12 / 223 (5.38%)	9 / 220 (4.09%)
occurrences all number	21	10
Injection site erythema
subjects affected / exposed	15 / 223 (6.73%)	20 / 220 (9.09%)
occurrences all number	47	53
Fatigue
subjects affected / exposed	42 / 223 (18.83%)	33 / 220 (15.00%)
occurrences all number	63	39
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	12 / 223 (5.38%)	14 / 220 (6.36%)
occurrences all number	18	14
Epistaxis
subjects affected / exposed	22 / 223 (9.87%)	22 / 220 (10.00%)
occurrences all number	29	36
Dyspnoea
subjects affected / exposed	26 / 223 (11.66%)	23 / 220 (10.45%)
occurrences all number	30	26
Cough
subjects affected / exposed	39 / 223 (17.49%)	25 / 220 (11.36%)
occurrences all number	47	30
Psychiatric disorders
Insomnia
subjects affected / exposed	21 / 223 (9.42%)	22 / 220 (10.00%)
occurrences all number	26	24
Investigations
Alanine aminotransferase increased
subjects affected / exposed	19 / 223 (8.52%)	11 / 220 (5.00%)
occurrences all number	52	13
Aspartate aminotransferase increased
subjects affected / exposed	17 / 223 (7.62%)	11 / 220 (5.00%)
occurrences all number	42	13
White blood cell count decreased
subjects affected / exposed	16 / 223 (7.17%)	11 / 220 (5.00%)
occurrences all number	28	49
Platelet count decreased
subjects affected / exposed	33 / 223 (14.80%)	22 / 220 (10.00%)
occurrences all number	115	48
Neutrophil count decreased
subjects affected / exposed	33 / 223 (14.80%)	19 / 220 (8.64%)
occurrences all number	93	67
Blood creatinine increased
subjects affected / exposed	22 / 223 (9.87%)	14 / 220 (6.36%)
occurrences all number	36	15
Blood bilirubin increased
subjects affected / exposed	14 / 223 (6.28%)	6 / 220 (2.73%)
occurrences all number	24	10
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	13 / 223 (5.83%)	12 / 220 (5.45%)
occurrences all number	16	15
Contusion
subjects affected / exposed	20 / 223 (8.97%)	10 / 220 (4.55%)
occurrences all number	25	12
Nervous system disorders
Headache
subjects affected / exposed	26 / 223 (11.66%)	20 / 220 (9.09%)
occurrences all number	38	22
Dizziness
subjects affected / exposed	19 / 223 (8.52%)	25 / 220 (11.36%)
occurrences all number	22	30
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	73 / 223 (32.74%)	77 / 220 (35.00%)
occurrences all number	182	191
Leukopenia
subjects affected / exposed	10 / 223 (4.48%)	14 / 220 (6.36%)
occurrences all number	30	23
Febrile neutropenia
subjects affected / exposed	15 / 223 (6.73%)	17 / 220 (7.73%)
occurrences all number	25	20
Anaemia
subjects affected / exposed	78 / 223 (34.98%)	82 / 220 (37.27%)
occurrences all number	154	214
Thrombocytopenia
subjects affected / exposed	71 / 223 (31.84%)	74 / 220 (33.64%)
occurrences all number	138	146
Gastrointestinal disorders
Nausea
subjects affected / exposed	78 / 223 (34.98%)	63 / 220 (28.64%)
occurrences all number	111	89
Haemorrhoids
subjects affected / exposed	18 / 223 (8.07%)	6 / 220 (2.73%)
occurrences all number	20	7
Diarrhoea
subjects affected / exposed	61 / 223 (27.35%)	51 / 220 (23.18%)
occurrences all number	87	88
Constipation
subjects affected / exposed	82 / 223 (36.77%)	90 / 220 (40.91%)
occurrences all number	126	134
Abdominal pain upper
subjects affected / exposed	13 / 223 (5.83%)	12 / 220 (5.45%)
occurrences all number	13	14
Abdominal pain
subjects affected / exposed	22 / 223 (9.87%)	15 / 220 (6.82%)
occurrences all number	24	16
Stomatitis
subjects affected / exposed	16 / 223 (7.17%)	7 / 220 (3.18%)
occurrences all number	30	9
Vomiting
subjects affected / exposed	51 / 223 (22.87%)	46 / 220 (20.91%)
occurrences all number	71	68
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	15 / 223 (6.73%)	14 / 220 (6.36%)
occurrences all number	45	14
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	35 / 223 (15.70%)	30 / 220 (13.64%)
occurrences all number	43	36
Back pain
subjects affected / exposed	25 / 223 (11.21%)	18 / 220 (8.18%)
occurrences all number	34	25
Myalgia
subjects affected / exposed	14 / 223 (6.28%)	10 / 220 (4.55%)
occurrences all number	26	12
Pain in extremity
subjects affected / exposed	18 / 223 (8.07%)	22 / 220 (10.00%)
occurrences all number	21	25
Infections and infestations
Urinary tract infection
subjects affected / exposed	22 / 223 (9.87%)	15 / 220 (6.82%)
occurrences all number	37	20
Upper respiratory tract infection
subjects affected / exposed	20 / 223 (8.97%)	21 / 220 (9.55%)
occurrences all number	24	25
Pneumonia
subjects affected / exposed	11 / 223 (4.93%)	19 / 220 (8.64%)
occurrences all number	12	20
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	29 / 223 (13.00%)	19 / 220 (8.64%)
occurrences all number	52	24
Hyperuricaemia
subjects affected / exposed	11 / 223 (4.93%)	15 / 220 (6.82%)
occurrences all number	12	18
Decreased appetite
subjects affected / exposed	38 / 223 (17.04%)	24 / 220 (10.91%)
occurrences all number	43	26
Abnormal loss of weight
subjects affected / exposed	7 / 223 (3.14%)	12 / 220 (5.45%)
occurrences all number	10	14
Hypomagnesaemia
subjects affected / exposed	16 / 223 (7.17%)	12 / 220 (5.45%)
occurrences all number	24	15
Hypophosphataemia
subjects affected / exposed	17 / 223 (7.62%)	7 / 220 (3.18%)
occurrences all number	54	10

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Were there any global substantial amendments to the protocol? Yes

17 Aug 2018

The following changes were made as per Amendment 5: 1. Changed ORR by Cycle 6 from a primary endpoint of the study to a secondary endpoint of the study. 2. Provided a brief summary of the benefit-risk ratio of the combination of pevonedistat and azacitidine. 3. Removed an inconsistency between exclusion criterion 1 and exclusion criterion 7 and require that patients who are participating in any interventional study 14 days before the first dose of study drug be excluded from participation in the study. 4. Removed the sentence about completing a protocol deviation form. 5. Changed SAE reporting from a paper-based system to electronic data capture. 6. Added all response rates to the disclosures information for all primary and secondary endpoints.

31 Mar 2020

The following changes were made as per Amendment 7: 1. Updated sample and event size estimations for EFS and OS events in the ITT population, and updated estimates of length of time for patient accrual and follow-up. 2. Removed the calculation of quality-adjusted life-years (QALYs) from the planned analyses for patient-reported outcomes (PROs). 3. Added nonserious treatment-emergent adverse events (TEAEs) (≥5% in any arm) to the categories planned for safety analyses/tabulations. 4. Updated vial volume and dilution instructions for pevonedistat to include a vial volume of 4.4 milliliters (mL) and a diluent of 0.9% saline solution.

29 Sep 2020

The following changes were made as per Amendment 10: 1. Specified that alternative monitoring approaches such as remote source data verification may be used in the event a monitor cannot visit the site in a timely manner due to the COVID-19 pandemic. 2. Specified that nonessential protocol visits that do not require on-site sample collection and assessment may be completed via telemedicine.

26 Mar 2021

The following changes were made as per Amendment 12: 1. Updated and clarified text on the posttrial access (PTA) program and its duration. 2. Changed the alpha spending approach by using a 1-sided alpha of 0.0001 to test OS at second interim analysis (IA2) and the remaining 1-sided alpha of 0.0249 at the OS final analysis (FA), instead of using the O’Brien Fleming (OBF) method. 3. Removed EFS analyses in the HR MDS/CMML subpopulation from the multiple hierarchical testing procedures for IA2 and FA.

26 May 2021

The following changes were made as per Amendment 13: 1. Added clarification to outline the statistical analysis if the prespecified number of approximately 202 OS events for FA are expected (based on blinded study data) to be available close to the IA2, the IA2 (i.e., EFS FA) and the FA (i.e., OS FA) will be performed as a single analysis, when approximately 202 OS events and the adaptive EFS event size have occurred in patients with HR MDS. As originally planned, separate multiple hierarchical testing procedures for the United States (US) submission and the ex-US submission will be used to test the primary endpoint of EFS and the key secondary endpoint of OS in the HR MDS population (US submission), the ITT population (ex-US submission), and other disease populations at this single analysis, with a total 1-sided alpha of 0.025 for each procedure.

21 Sep 2021

The following changes were made as per Amendment 14: 1. Updated the name of the legal entity to Takeda Development Center Americas, Inc., 95 Hayden Avenue, Lexington, MA 02421.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Event-Free Survival (EFS)

Primary: Event-Free Survival (EFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60

Secondary: Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60

Secondary: Kaplan-Meier Estimates of Six-Month Survival Rate

Secondary: Kaplan-Meier Estimates of Six-Month Survival Rate

Secondary: Kaplan-Meier Estimates of One-Year Survival Rate

Secondary: Kaplan-Meier Estimates of One-Year Survival Rate

Secondary: Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30

Secondary: Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30

Secondary: 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

Secondary: 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

Secondary: Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi)

Secondary: Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi)

Secondary: Number of Participants With CR and Marrow CR

Secondary: Number of Participants With CR and Marrow CR

Secondary: Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI)

Secondary: Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI)

Secondary: Number of Participants With CR and Marrow CR and PR

Secondary: Number of Participants With CR and Marrow CR and PR

Secondary: Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI)

Secondary: Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI)

Secondary: Number of Participants With Overall Response (OR)

Secondary: Number of Participants With Overall Response (OR)

Secondary: Number of Participants With Overall Response 2 (OR2)

Secondary: Number of Participants With Overall Response 2 (OR2)

Secondary: Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi)

Secondary: Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi)

Secondary: Duration of Complete Remission (CR)

Secondary: Duration of Complete Remission (CR)

Secondary: Duration of Overall Response (OR)

Secondary: Duration of Overall Response (OR)

Secondary: Duration of Overall Response 2 (OR2)

Secondary: Duration of Overall Response 2 (OR2)

Secondary: Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence

Secondary: Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence

Secondary: Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence

Secondary: Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence

Secondary: Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi)

Secondary: Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi)

Secondary: Number of Participants With Hematologic Improvement (HI)

Secondary: Number of Participants With Hematologic Improvement (HI)

Secondary: Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML

Secondary: Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML

Secondary: Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death

Secondary: Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death

Secondary: 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

Secondary: 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

Secondary: Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

Secondary: Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

Secondary: 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

Secondary: 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

Secondary: Number of Participants With Overall Response by Cycle 6

Secondary: Number of Participants With Overall Response by Cycle 6

Secondary: Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

Secondary: Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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