Clinical Trial Results:
A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute Myelogenous Leukemia
Summary
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EudraCT number |
2015-000221-37 |
Trial protocol |
CZ NL ES BE DE IE BG FR IT |
Global end of trial date |
23 Jul 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Jul 2022
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First version publication date |
28 Jul 2022
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
Pevonedistat-2001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02610777 | ||
WHO universal trial number (UTN) |
U1111-1169-6540 | ||
Other trial identifiers |
REec: REec-2016-2145, Israel: Pevonedistat-2001CTID | ||
Sponsors
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Sponsor organisation name |
Millennium Pharmaceuticals, Inc.
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Sponsor organisation address |
40 Landsdowne Street, Cambridge, MA, United States, 02139
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Public contact |
Study Director, Takeda, TrialDisclosures@takeda.com
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Scientific contact |
Study Director, Takeda, TrialDisclosures@takeda.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Jul 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Jul 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The objective of this study is to evaluate the efficacy and safety of pevonedistat plus azacitidine versus single-agent azacitidine in participants with HR-MDS or CMML, or low-blast AML.
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Protection of trial subjects |
All the participants were required to read and sign the Informed Consent Form (ICF).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
04 Apr 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 6
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Country: Number of subjects enrolled |
United States: 45
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Country: Number of subjects enrolled |
Belgium: 10
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Country: Number of subjects enrolled |
Bulgaria: 15
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Country: Number of subjects enrolled |
Germany: 1
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Country: Number of subjects enrolled |
Spain: 22
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Ireland: 1
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Country: Number of subjects enrolled |
Israel: 3
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Country: Number of subjects enrolled |
Italy: 11
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Country: Number of subjects enrolled |
Czechia: 4
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Worldwide total number of subjects |
120
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EEA total number of subjects |
66
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
27
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From 65 to 84 years |
92
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85 years and over |
1
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Recruitment
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Recruitment details |
Participants took part in the study at 45 investigative sites in the United States [US], Canada, Belgium, Bulgaria, Czech Republic, Germany, France, Israel, Italy, Spain, and Ireland from 14 April 2016 to 23 July 2021. | ||||||||||||||||||||||||||||||
Pre-assignment
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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
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Azacitidine 75 mg/m^2 | ||||||||||||||||||||||||||||||
Arm description |
Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML). | ||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Azacitidine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
Azacitidine intravenous or subcutaneous formulation.
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Arm title
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Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2 | ||||||||||||||||||||||||||||||
Arm description |
Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML). | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pevonedistat
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
Pevonedistat intravenous or subcutaneous formulation.
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Investigational medicinal product name |
Azacitidine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
Azacitidine intravenous or subcutaneous formulation.
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Baseline characteristics reporting groups
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Reporting group title |
Azacitidine 75 mg/m^2
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Reporting group description |
Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
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Reporting group description |
Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Azacitidine 75 mg/m^2
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Reporting group description |
Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML). | ||
Reporting group title |
Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
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Reporting group description |
Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML). |
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End point title |
Overall Survival (OS) | ||||||||||||
End point description |
OS was defined as the time from the date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis were censored at the date the participant was last known to be alive. The Kaplan Meier estimates was used for the analysis. ITT Population was defined as all participants who were randomized.
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End point type |
Primary
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End point timeframe |
From date of randomization until death (up to approximately 5 years)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.464 [1] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.861
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.577 | ||||||||||||
upper limit |
1.286 | ||||||||||||
Notes [1] - Hazard Ratio (HR) was based on an unstratified Cox proportional hazard regression model with treatment as a factor. P-value is from an unstratified log-rank test. |
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End point title |
Event-Free Survival (EFS) | ||||||||||||
End point description |
EFS is defined as the time from the date of randomization to the date of the occurrence of an event. An event is defined as death or transformation to AML for HR MDS/CMML participants, whichever occurs first, or defined as death for low-blast AML participants. HR MDS/CMML participants without documented EFS event will be censored at the date of the last response assessment. HR MDS/CMML participants with no response assessment and no death will be censored at the date of randomization. Low-blast AML participants without documentation of death will be censored at the date the participant was last known to be alive. HR MDS/CMML participants who received alternative antineoplastic therapy before death or transformation to AML will be censored at the date of last adequate assessment prior to starting alternate antineoplastic therapy. The Kaplan-Meier estimate was used for the analysis. ITT Population was defined as all participants who were randomized.
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End point type |
Secondary
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End point timeframe |
From date of randomization until transformation to AML, or death due to any cause (up to approximately 5 years)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.092 [2] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.706
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.469 | ||||||||||||
upper limit |
1.061 | ||||||||||||
Notes [2] - P-value is based on the unstratified log-rank test. HR:unadjusted stratified Cox proportional hazard regression with treatment as factor.HR<1:better prevention of EFS in combination arm than azacitidine arm. |
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End point title |
Six-month Survival Rate | ||||||||||||
End point description |
Six-month survival rate was defined as the percentage of participants that survived at the end of the Month 6 from randomization. Percentage of participants was based on Kaplan-Meier estimate of probability. ITT Population was defined as all participants who were randomized. Overall number analyzed are the number of participants with data available for analyses.
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End point type |
Secondary
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End point timeframe |
Month 6
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No statistical analyses for this end point |
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End point title |
One-year Survival Rate | ||||||||||||
End point description |
One-year survival rate was defined as the percentage of participants that survived at the end of the first year from randomization. Percentage of participants was based on Kaplan-Meier estimate of probability. ITT Population was defined as all participants who were randomized. Overall number analyzed are the number of participants with data available for analyses.
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End point type |
Secondary
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End point timeframe |
Month 12
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No statistical analyses for this end point |
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End point title |
Time to AML Transformation in HR MDS or CMML Participants | ||||||||||||
End point description |
Time to AML transformation in HR MDS and CMML participants is defined as time from randomization to documented AML transformation. Participants without documented AML transformation at the time of the analysis are censored at the date of the last assessment. Participants who died before progression to AML are censored at the date of death. Transformation to AML is defined, according to World Health Organization (WHO) classification, as a participant having >20% blasts in the blood or marrow and increase of blast count by 50%. ITT Population was defined as all participants who were randomized. Overall number of participants analyzed is the number of participants with data available for analyses. 999= The median, lower limit and upper limit of 95% confidence interval (CI) was not estimable due to lower number of participants with the event.
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End point type |
Secondary
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End point timeframe |
From date of randomization until transformation to AML (up to approximately 5 years)
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
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Number of subjects included in analysis |
84
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.267 [3] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.562
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.2 | ||||||||||||
upper limit |
1.579 | ||||||||||||
Notes [3] - P-value is from an unstratified log-rank test. Hazard ratio (HR) is based on an unstratified Cox proportional hazard regression model with treatment as a factor. |
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End point title |
Percentage of Participants With Complete Remission (CR) | ||||||||||||
End point description |
Disease responses for HR MDS or CMML=based on the modified International Working Group (IWG) response criteria for MDS and for low-blast AML on the revised IWG response criteria for AML.CR for HR MDS or CMML:≤5% myeloblasts with normal maturation of all cell lines in the bone marrow ≥11 gram/deciliter (g/dL) hemoglobin (Hb), ≥100*10^9/liter (/L) platelets (plt), ≥1.0*10^9/L absolute neutrophil count (ANC) and 0% blasts in peripheral blood.CR for low-blast AML: morphologic leukemia-free state,ANC of more than 1.0*10^9/L and plt of ≥1.0*10^9/L,transfusion independence,and no residual evidence of extramedullary leukemia.CR with incomplete blood count recovery for low-blast AML:some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP)(<100*10^9/L).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.
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End point type |
Secondary
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End point timeframe |
From date of randomization until CR (up to approximately 5 years)
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
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Number of subjects included in analysis |
108
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.312 [4] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Absolute Rate Difference | ||||||||||||
Point estimate |
9.61
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-8.83 | ||||||||||||
upper limit |
28.04 | ||||||||||||
Notes [4] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone. |
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End point title |
Percentage of Participants With CR and Partial Remission (PR) | ||||||||||||
End point description |
Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML:≤5% myeloblasts with normal maturation of all cell lines in bone marrow, ≥11 g/dL Hb; ≥100*10^9/L plt; ≥1.0*10^9/L ANC and 0% blasts in peripheral blood. PR for HR MDS/CMML:considered achieved if all CR criteria is met except for bone marrow blasts decreased by ≥50%over pretreatment but still >5%. CR for low-blast AML:morphologic leukemia-free state, ANC of >1.0*10^9/L and plt of≥100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CRi for low-blast AML:fulfill criteria for CR except for residual neutropenia (<100*10^9/L)/TTP(<100*10^9/L). PR for low-blast AML:all hematological values for CR but with decrease of ≥50% in percentage of blasts to 5%-25% in bone marrow aspirate. REP: all participants who received ≥1 dose of study drug, had Baseline and ≥1 postbaseline disease assessment.
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End point type |
Secondary
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End point timeframe |
From date of randomization until CR and PR (up to approximately 5 years)
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
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Number of subjects included in analysis |
108
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.56 [5] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Absolute Rate Difference | ||||||||||||
Point estimate |
5.63
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-13.19 | ||||||||||||
upper limit |
24.44 | ||||||||||||
Notes [5] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone. |
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End point title |
Percentage of Participants With Overall Response | ||||||||||||
End point description |
Disease responses (HR MDS/CMML): modified IWG criteria for MDS; low-blast (LB) AML: revised IWG criteria for AML. Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with Cri+PR.HR MDS/CMML-CR:≤5%myeloblasts with normal maturation of bone marrow (BM) cell lines,≥11g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L ANC,0% blasts in peripheral blood; PR:CR criteria met except BM blasts≥50%less over pretreatment but still>5%; HI:hb increase (inc)≥1.5g/dL if baseline<11g/dL;plt inc≥30*10^9/L if baseline>20*10^9/L/Inc. from <20*10^9/L->20*10^9/L, ANC inc. by 100%;absolute inc. of>0.5*10^9/L if baseline<100*10^9/L. LB AML-CR:morphologic leukemia-freestate>1.0*10^9ANC, ≥100*10^9/L plt, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR hematological values but≥50%less in BM aspirate. REP: all participants who received ≥1 dose of study drug, had Baseline and ≥1 postbaseline disease assessment.
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End point type |
Secondary
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End point timeframe |
From date of randomization until CR, PR, or hematologic improvement (HI) (up to approximately 5 years)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
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Number of subjects included in analysis |
108
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.343 [6] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Absolute Rate Difference | ||||||||||||
Point estimate |
8.64
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-9.09 | ||||||||||||
upper limit |
26.38 | ||||||||||||
Notes [6] - P-value was obtained from a stratified Cochran-Mantel-Haenszel chi-square test stratified by low-blast AML. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone. |
|
|||||||||||||
End point title |
Percentage of Participants With CR in low-blast AML | ||||||||||||
End point description |
Disease response for low-blast AML is based on the revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP) (<100*10^9/L). REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Overall number analyzed are the number of participants with data available for analyses.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until CR (up to approximately 5 years)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
32
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.296 [7] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Absolute Rate Difference | ||||||||||||
Point estimate |
-18.82
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-52.91 | ||||||||||||
upper limit |
15.26 | ||||||||||||
Notes [7] - P-value is from an unstratified Cochran-Mantel-Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone. |
|
|||||||||||||
End point title |
Percentage of Participants With CR by Cycle 4 | ||||||||||||
End point description |
Disease responses for HR MDS or CMML were based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=100*10^9/L plt, ANC >=1.0*10^9/L and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Overall number (N) analyzed is the number of participants with data available for analyses.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until CR by Cycle 4 (cycle length is equal to [=] 28 days)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
76
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.152 [8] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Absolute Rate Difference | ||||||||||||
Point estimate |
13.16
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-4.49 | ||||||||||||
upper limit |
30.81 | ||||||||||||
Notes [8] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone. |
|
|||||||||||||
End point title |
Percentage of Participants With CR and PR by Cycle 4 | ||||||||||||
End point description |
Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML:≤5% myeloblasts with normal maturation of all cell lines in BM,≥11 g/dL Hb;≥100*10^9/L plt;≥1.0*10^9/L ANC and 0% blasts in peripheral blood.PR for HR MDS/CMML:achieved if all CR criteria is met except for BM blasts decreased by≥50% over pretreatment but still>5%.CR for low-blast AML:morphologic leukemia-free state,ANC of>1.0*10^9/L and plt of≥100*10^9/L,transfusion independence,no residual evidence of extramedullary leukemia.CRi for low-blast AML:fulfill all criteria for CR except for residual neutropenia (<100*10^9/L)/TTP (<100*10^9/L).PR for low-blast AML:all hematological values for CR but with decrease of ≥50% in percentage of blasts to 5%-25% in BM aspirate.REP:all participants who received ≥1 dose of study drug,had Baseline and ≥1 postbaseline disease assessment.N=number of participants with data available for analyses.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until CR and PR, by Cycle 4 (cycle length=28 days)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
76
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.301 [9] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Absolute Rate Difference | ||||||||||||
Point estimate |
10.53
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-9.13 | ||||||||||||
upper limit |
30.18 | ||||||||||||
Notes [9] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone. |
|
|||||||||||||
End point title |
Percentage of Participants With Overall Response by Cycle 4 | ||||||||||||
End point description |
Disease responses (HR MDS/CMML): modified IWG criteria for MDS;LB AML:revised IWG criteria for AML.Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with Cri+PR.HR MDS/CMML-CR:≤5%myeloblasts with normal maturation of BM cell lines,≥11g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L ANC,0% blasts in peripheral blood;PR:CR criteria met except BM blasts≥50%less over pretreatment but still>5%; HI:hb inc≥1.5g/dL if baseline<11g/dL;plt inc≥30*10^9/L if baseline>20*10^9/L/Inc. from <20*10^9/L->20*10^9/L,ANC inc. by 100%;absolute inc. of>0.5*10^9/L if baseline<100*10^9/L.LB AML-CR:morphologic leukemia-freestate>1.0*10^9ANC,≥100*10^9/L plt,transfusion independence,no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR hematological values but≥50%less in BM aspirate.REP was analysed.N=number of participants with data available for analyses.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until CR, PR or HI, by Cycle 4 (cycle length=28 days)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
76
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.254 [10] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Absolute Rate Difference | ||||||||||||
Point estimate |
13.16
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-9.12 | ||||||||||||
upper limit |
35.44 | ||||||||||||
Notes [10] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone. |
|
|||||||||||||
End point title |
Percentage of Participants With CR in low-blast AML by Cycle 4 | ||||||||||||
End point description |
Disease response for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and ptl of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for low blast AML participants which is included as the overall number of participants analyzed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From the date of randomization until CR by Cycle 4 (cycle length=28 days)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
32
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.787 [11] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Absolute Rate Difference | ||||||||||||
Point estimate |
-4.71
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-38.33 | ||||||||||||
upper limit |
28.92 | ||||||||||||
Notes [11] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone. |
|
|||||||||||||
End point title |
Duration of Complete Remission (CR) | ||||||||||||
End point description |
Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML) or relapse after CR or PR (participants with HR MDS/CMML). Disease responses for HR MDS or CMML are based on the Modified IWG Response Criteria for MDS and for low-blast AML on the Revised IWG Response Criteria for AML.CR for HR MDS or CMML≤5% myeloblasts with normal maturation of all cell lines in the bone marrow,≥11 g/dL Hgb,≥100*10^9/L pl,≥1.0*10^9/L neutrophils;0% blasts in peripheral blood.CR for low-blast AML:morphologic leukemia-free state,neutrophils of<1.0*10^9/L;pl of≥100*10^9/L,transfusion independence,no residual evidence of extramedullary leukemia.CRi for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (pl<100*10^9/L). REP was analysed.N=complete responders.999=upper limit of full range was not estimable due to lower number of participants with event.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until CR (up to approximately 5 years)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
44
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.62 [12] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.789
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.308 | ||||||||||||
upper limit |
2.02 | ||||||||||||
Notes [12] - P-value is from an unstratified log-rank test. Hazard ratio was based on an unstratified Cox proportional hazard regression model and treatment as a factor in the model. |
|
|||||||||||||
End point title |
Duration of Complete Remission (CR) and Partial Remission (PR) | ||||||||||||
End point description |
Duration of CR=first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML).Disease responses (HR MDS/CMML) are based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.For HR MDS/CMML-CR:≤5%myeloblasts with normal maturation of all BM cell lines,≥11 g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L neutrophils,0% blasts in peripheral blood;PR:all CR criteria met except BM blasts ≥50% decrease over pretreatment but still >5%;low-blast AML-CR:morphologic leukemia-free state,>1.0*10^9/L ANC,plt ≥100*10^9/L,transfusion independence,no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia <1.0*10^9/L/TTP <100*10^9/L;PR:all CR hematological values but with a decrease of ≥50% in blasts percentage to 5%-25% in bone marrow aspirate. REP was analysed.N=CR and PR responders. 999=Upper limit of full range was not estimable due to lower number of participants with event.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until CR or PR (up to approximately 5 years)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
52
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.436 [13] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.719
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.313 | ||||||||||||
upper limit |
1.653 | ||||||||||||
Notes [13] - P-value is from an unstratified log-rank test. Hazard ratio was based on an unstratified Cox proportional hazard regression model and treatment as a factor in the model. |
|
|||||||||||||
End point title |
Duration of Overall Response | ||||||||||||
End point description |
OR Duration:Response(RE)to first documentation of PD/relapse(RS)fromCR for low-blast(LB)AML/RS afterCR/PR forHRMDS/CMML.Disease REs(HRMDS/CMML):modifiedIWG criteria(CA) forMDS;LBAML:revisedIWG CA forAML.Overall RE(HRMDS/CMML)=CR,PR/HI,LB AML=CR+CR Cri+PR.HRMDS/CMML-CR:≤5%myeloblasts withBMcell lines’ normal maturation,≥11g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L ANC,0%blasts(bs) in peripheral blood;PR:CR CA met except BM bs≥50%less over pretreatment,still>5%; HI:hb increase(IE)≥1.5g/dL if baseline(BL)<11g/dL;plt IE≥30*10^9/L if BL>20*10^9/L IEfrom<20*10^9/L->20*10^9/L,ANC IEby100%;absoluteIE>0.5*10^9/L ifBL<100*10^9/L.LBAML-CR:MorphologicLeukemia(LA)-freestate>1.0*10^9 ANC,≥100*1^9/Lplt,transfusion independence,no extramedullaryLA residual(RL)evidence;CRi:fulfil CR CAexcept RLneutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR HematologicValues,≥50%less in BM aspirate.SubjectsAnalyzed=REP responders.999=full range UpperLimit inestimable,less subjects with event.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until CR, PR or HI (up to approximately 5 years)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
72
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.565 [14] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.81
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.395 | ||||||||||||
upper limit |
1.662 | ||||||||||||
Notes [14] - P-value is from an unstratified log-rank test. Hazard ratio was based on an unstratified Cox proportional hazard regression model and treatment as a factor in the model. |
|
|||||||||||||
End point title |
Duration of Complete Remission (CR) in Low-blast AML | ||||||||||||
End point description |
Disease responses for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for AML participants which is included as the overall number of participants analyzed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until CR (up to approximately 5 years)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
8
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.383 [15] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.42
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.057 | ||||||||||||
upper limit |
3.109 | ||||||||||||
Notes [15] - P-value is from an unstratified log-rank test. Hazard ratio was based on an unstratified Cox proportional hazard regression model and treatment as a factor in the model. |
|
|||||||||||||
End point title |
Time to First CR or PR | ||||||||||||
End point description |
Time to first CR or PR: time from randomization to first documented CR or PR, whichever occurs first. Disease responses (HR MDS/CMML) based on modified IWG response criteria for MDS; low-blast AML on revised IWG response criteria for AML. HR MDS/CMML-CR:≤5% myeloblasts with normal maturation of all BM cell lines,≥11 g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L ANC,0% blasts in peripheral blood;PR: all CR criteria met except BM blasts ≥50% decrease over pretreatment but still >5%;For low-blast AML-CR:morphologic leukemia-free state,>1.0*10^9/L ANC, plt ≥100*10^9/L, transfusion independence,no residual evidence of extramedullary leukemia;CR with incomplete blood count recovery:fulfill CR criteria except residual neutropenia <1.0*10^9/L/TTP <100*10^9/L; PR:all CR hematological values but with a decrease of ≥50% in the percentage of blasts to 5% to 25% in the BM aspirate.REP was analysed.999=Upper limit of 95% CI was not estimable due to lower number of participants with event.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until CR or PR (up to approximately 5 years)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
108
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [16] | ||||||||||||
P-value |
= 0.498 [17] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.206
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.699 | ||||||||||||
upper limit |
2.081 | ||||||||||||
Notes [16] - HR is based on an unstratified Cox proportional hazard regression model with treatment as a factor. HR>1 for the treatment indicates a shorter time to first CR, CRi or PR in the Pevonedistat Combination arm compared to the Azacitidine only arm. [17] - P-value is from an unstratified log-rank test. |
|
|||||||||||||
End point title |
Time to Subsequent Therapy | ||||||||||||
End point description |
Time to subsequent therapy is defined as time from randomization to the date of the first subsequent therapy. Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity. Participants who discontinue study treatment to receive single-agent azacitidine off study did not be counted as receiving subsequent therapy. ITT Population was defined as all participants who were randomized. 999=The median, lower limit and upper limit of 95% CI was not estimable due to lower number of participants with the event.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization up to approximately 5 years
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
HR is based on an unstratified Cox proportional hazard regression model with treatment as a factor. HR>1 for the treatment indicates a shorter time to first CR, CRi or PR in the Pevonedistat Combination arm compared to the Azacitidine only arm.
|
||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.888 [18] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.905
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.226 | ||||||||||||
upper limit |
3.62 | ||||||||||||
Notes [18] - P-value is from an unstratified log-rank test. |
|
|||||||||||||||||||
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. Overall number analyzed are the number of participants from a subset of the ITT Population who were transfusion dependent at Baseline. Number analyzed is the number of participants who were transfusion dependent at Baseline for the specified category.
|
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End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
8 weeks before randomization through 30 days after last dose of any study drug (up to approximately 5 years)
|
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|
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||||||||
Statistical analysis description |
Percentage of Participants With Platelet-transfusion Independence
|
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Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||||||||
Number of subjects included in analysis |
52
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.454 [19] | ||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||
Parameter type |
Absolute Rate Difference | ||||||||||||||||||
Point estimate |
20
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
-26.381 | ||||||||||||||||||
upper limit |
66.381 | ||||||||||||||||||
Notes [19] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. |
|||||||||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||||
Statistical analysis description |
Percentage of Participants With RBCs-transfusion Independence
|
||||||||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||||||||
Number of subjects included in analysis |
52
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.162 [20] | ||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||
Parameter type |
Absolute Rate Difference | ||||||||||||||||||
Point estimate |
19.231
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
-6.925 | ||||||||||||||||||
upper limit |
45.386 | ||||||||||||||||||
Notes [20] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. |
|
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End point title |
Percentage 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%. Percentage of participants was calculated as the total number of events divided by the total number of subject-years in each group. ITT Population included all participants who were randomized.
|
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End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until transformation to AML or until initiation of subsequent therapy (up to approximately 5 years)
|
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|
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No statistical analyses for this end point |
|
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End point title |
Time to Progressive Disease (PD), Relapse, or Death | ||||||||||||
End point description |
Time from randomization until PD/transformation to AML/relapse/death due to any cause, whichever occurs first. Relapse after CR or PR in MDS/CMML: return to pretreatment bone marrow blast % or decrement of >=50% from maximum remission levels in ANC or plt, reduction in Hb concentration by >=1.5 g/dL or transfusion dependence. PD: at least 50% decrement from maximum remission in ANC or plt, or reduction in Hb by>=2g/dL or transfusion dependence;participants with <5% blasts: >=50% increase (inc) in blasts to >5%; 5%-10%: >=50% inc to >10%; 10%-20%: >=50% inc to>20%;20%-30%:>=50% inc to >30%. Relapse after CR in Low blast AML: reappearance of leukemic blasts in peripheral blood or >=5% blasts in bone marrow not attributable to any cause (example, bone marrow regeneration after consolidation therapy). If there are no circulating blasts, bone marrow contains 5%-20% blasts, a repeat analysis is performed a week later. ITT Population was defined as all participants who were randomized.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From date of randomization until PD, relapse or death (up to approximately 5 years)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
|
||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [21] | ||||||||||||
P-value |
= 0.266 [22] | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.79
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.521 | ||||||||||||
upper limit |
1.198 | ||||||||||||
Notes [21] - HR is based on an unstratified Cox proportional hazard regression model with treatment as a factor. A HR<1for the treatment indicates a better prevention of PD, relapse after CR or PR, or death in the Pevonedistat Combination arm compared to the Azacitidine only arm. [22] - P-value is from an unstratified log-rank test. |
|
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End point title |
Number of Participants Reporting one or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | |||||||||||||||
End point description |
Adverse event=any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.SAE=any untoward medical occurrence that:results in death;is life-threatening;requires inpatient hospitalization or prolongation of existing hospitalization;results in persistent or significant disability/incapacity;leads to a congenital anomaly/birth defect in the offspring of the participant or is a medically important event that satisfies any of the following:a) May require intervention to prevent items 1 through 5 above.b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization.TEAE=any adverse event occurring after the start of pevonedistat administration of the treatment period.Safety Population=all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From date of randomization up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Number of Participants in the Safety Analysis Population With Clinically Significant Laboratory Abnormalities Reported as TEAEs | |||||||||||||||||||||
End point description |
Laboratory assessments included clinical chemistry, hematology, and urinalysis. Safety Population included all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
From first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
|
|||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||
End point title |
Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status | ||||||||||||||||||||||||||||||||||||
End point description |
Number of participants with change from Baseline in ECOG performance status was measured on 6 point scale to assess participant’s performance status, where: Grade 0(Normal activity. Fully active, able to carry on all pre-disease activities without restriction); Grade 1(Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); Grade 2(In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours); Grade 3(In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours); Grade 4(100% bedridden. Completely disabled, cannot carry on any self-care, totally confined to bed or chair); Grade 5(Dead). ITT population=all participants who were randomized in the Safety Population. Only categories for which there was at least 1 participant are reported.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
From first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values Reported as TEAEs | |||||||||||||||
End point description |
ECG assessments included QT, QRS duration, PR interval, ventricular rate, QTcB, QTcF. Safety Population included all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline Values in Vital Signs Reported as TEAEs | |||||||||||||||
End point description |
Vital signs assessments included diastolic and systolic blood pressure, heart rate, and body temperature. Safety Population included all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
|
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Adverse event reporting additional description |
At each visit the investigator had to document any occurrence of adverse events, abnormal laboratory findings, and vital signs. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
|
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Reporting groups
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Reporting group title |
Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
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Reporting group description |
Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Azacitidine 75 mg/m^2
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Reporting group description |
Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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21 Oct 2015 |
The following changes were made in amendment 1: Revise study population to include participants with low-blast acute myelogenous leukemia (AML). Revise the number of participants expected to be enrolled in the study. Clarify definition of progressive disease for participants with low-blast AML. Clarify timing of event-free survival (EFS) visit for participants with higher-risk MDS (HR MDS), chronic myelomonocytic leukemia (CMML), or AML. Revise primary endpoint to reflect the addition of participants with low-blast AML. Revise secondary endpoints to reflect the addition of participants with low-blast AML. Delete secondary endpoint regarding collection of pevonedistat plasma concentrations since this information is captured in a secondary objective. Update statistical methods section to revise hazard ratio calculations and confidence intervals along with the estimated number of EFS events required. Add description of analyses for secondary efficacy endpoints. Revise section on timing of interim analyses (IA). |
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13 Sep 2016 |
Clarify that relapse includes relapse from complete remission (CR) and partial remission (PR) for participants with MDS/CMML, and relapse from CR for participants with AML. Add cytogenetic CR as an exploratory objective and endpoint. Add evaluation of minimal residual disease in participants who achieve CR in Cycle 4 or Cycle 7 as an exploratory objective and endpoint. Add relapse after CR as a response criterion for AML.
Add cytogenetic CR as a response criterion for AML. |
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16 Nov 2017 |
Realign the analysis of the primary objective and endpoint as related to the change in the definition of an event for participants with low-blast AML. Specify the change in the follow-up process for participants with low-blast AML. Specify the trigger initiating the timing of the overall survival final analysis and other factor(s) that might affect the duration of the study. Clarify that Kaplan-Meier estimates and CIs of 6-month and 1-year survival rates will be provided based on the intent-to-treat population. |
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27 Jul 2018 |
The following changes were made in amendment 4: Clarify definition of safety population for purposes of analysis. Specify changes in general methodology for analysis of efficacy. Specify analyses of primary efficacy endpoint OS. Clarify methodology for analysis of secondary efficacy endpoints, including those that are response-related. Clarify populations for analyses of health-related quality of life. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |