Leukemia, Myeloid, Acute, Leukemia, Myelomonocytic, Chronic, Myelodysplastic Syndrome
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is 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 AML in participants with MDS or CMML, whichever occurs first, and is defined as death in participants with low-blast AML).
Detailed description
The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to treat people with higher-risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML) and low-blast acute myelogenous leukemia (AML) as a combination treatment with azacitidine. This study will look at the overall survival, event-free survival and response to treatment in people who take pevonedistat and azacitidine when compared to people who take single-agent azacitidine. The study will enroll approximately 450 participants. Once enrolled, participants will be randomly assigned in 1:1 ratio (by chance, like flipping a coin) to one of the two treatment groups in 28-day treatment cycles: * Pevonedistat 20 mg/m\^2 and azacitidine 75 mg/m\^2 combination * Single-agent azacitidine 75 mg/m\^2 All participants will receive azacitidine via intravenous or subcutaneous route. Participants randomized to the combination arm will also receive pevonedistat intravenous infusion. This multi-center trial will be conducted Spain, Belgium, Brazil, Canada, Czech Republic, France, Germany, Israel, Italy, the United States, Australia, Greece, Japan, Mexico, Poland, Russia, Korea, Turkey, China and United Kingdom. The overall time to participate in this study is approximately 63 months. Participants will attend the end-of-treatment visit 30 days after the last dose of study drug or before the start of subsequent anti-neoplastic therapy if that occurs sooner. Participants with HR MDS or CMML will have EFS follow-up study visits every month if their disease has not transformed to AML and they have not started subsequent therapy. Participants with low-blast AML will have response follow-up study visits every month until they relapse from CR or meet the criteria for PD. All participants will enter OS follow-up (contacted every 3 months) when they have confirmed transformation to AML (for participants with HR MDS or CMML at enrollment) or experienced PD (for participants with low-blast AML at study enrollment).
Interventions
DRUGPevonedistat
Pevonedistat intravenous infusion.
DRUGAzacitidine
Azacitidine intravenous or subcutaneous formulation.
Sponsors
Takeda Development Center Americas, Inc.
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or CMML (i.e., with white blood cell \[WBC\] \<13,000/microliter \[mcL\]) or low-blast acute myelogenous leukemia (AML). 2. Has MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R): * Very high (\>6 points). * High (\>4.5-6 points). * Intermediate (\>3-4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of \>=5% bone marrow myeloblasts. 3. Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2. 4. Participants with AML (20%-30% blasts) must have a treatment-related mortality (TRM) score \>=4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers. Calculation of TRM score: * 0 for (age \<61 years), +2 for (age 61-70 years), +4 for (age \>=71 years). * \+ 0 for (PS=0), +2 for (PS=1), +4 for (PS \>1). * \+ 0 for (platelets \<50), +1 for (platelets \>=50).
Exclusion criteria
1. Has previous treatment for HR MDS or CMML or low-blast AML with chemotherapy or other antineoplastic agents including hypomethylating agent (HMAs) such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug. 2. Has acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis. 3. Participants with AML with a WBC count \>50,000/mcL. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria. 4. Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a participant is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors: * Age \>75. * Comorbidities. * Inability to tolerate intensive chemotherapy (e.g., participants with AML with 20%-30% blasts and TRM \>=4). * Physician decision (e.g., lack of available stem cell donor). * The reason a participant is not eligible should be documented in the electronic case report form (eCRF). 5. Has either clinical evidence of or history of central nervous system involvement by AML. 6. Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. 7. Is diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. 8. Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection. 9. Has prothrombin time (PT) or aPTT \>1.5× upper limit of normal (ULN) or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment. 10. Has known human immunodeficiency virus (HIV) seropositive. 11. Has known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Participants who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. 12. Has known hepatic cirrhosis or severe preexisting hepatic impairment. 13. Has known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension. 14. Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the first dose of pevonedistat.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | From randomization until transformation to acute myeloid leukemia, or death due to any cause: up to approximately 42 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimates of Six-Month Survival Rate | Month 6 | Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of Month 6 from randomization are presented. |
| Kaplan-Meier Estimates of One-Year Survival Rate | Year 1 | 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. |
| Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30 | Up to Day 30 | 30-day mortality was defined as number of participants who died within 30 days from the first dose of study drug. |
| Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60 | Up to Day 60 | 60-day mortality was defined as number of participants who died within 60 days from the first dose of study drug. |
| 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 | From randomization until transformation to AML (up to approximately 42 months) | Time to AML transformation in HR MDS and CMML participants was defined as time from randomization to documented AML transformation as determined by the independent review committee (IRC) assessment. Participants who died before progression to AML were censored. Transformation to AML was defined, according to WHO classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%. |
| Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi) | From randomization until CR (up to approximately 42 months) | 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). |
| Number of Participants With CR and Marrow CR | From randomization until CR or marrow CR (up to approximately 42 months) | 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. |
| Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI) | From randomization until, CR, PR or HI (up to approximately 42 months) | 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. |
| Number of Participants With CR and Marrow CR and PR | From randomization until CR or Marrow CR and PR (up to approximately 42 months) | 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%. |
| Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI) | From randomization until CR, marrow CR, PR or HI (up to approximately 42 months) | 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. |
| Number of Participants With Overall Response (OR) | From randomization until CR and PR or CR, CRi and PR (up to approximately 42 months) | Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR or PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still\>5%. For low-blast AML-CR:morphologic leukemia-free state\>1.0\*10\^9 neutrophils, \>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L or pl \<100\*10\^9/L; PR: all CR hematological values but \>=50% decrease in bone marrow aspirate. |
| Number of Participants With Overall Response 2 (OR2) | From randomization until, CR, PR or HI or CR, CRi or PR (up to approximately 42 months) | OR2=participant with best overall response of CR+PR+HI in HR MDS/CMML participants,or of CR+CRi+PR in low-blast AML participants.CR:≤5% myeloblasts with normal maturation of all bone marrow(BM)cell lines,≥11g/dL Hgb,≥100\*10\^9/L pl,≥1.0\*10\^9/L neutrophils,0% blasts in peripheral blood;PR:all CR criteria met except BM blasts ≥50% decrease over pretreatment but still \>5%;HI:Hgb increase(inc) ≥1.5g/dL if baseline(BL)\<11 g/dL;pl inc≥30\*10\^9/L if BL\>20\*10\^9/L or inc from \<20\*10\^9/L to \>20\*10\^9/L and by 100%;neutrophil inc by 100%;absolute inc of \>0.5\*10\^9/L if BL\<100\*10\^9/L.For low-blast AML-CR:morphologic leukemia-free state \>1.0\*10\^9 neutrophils,≥100\*10\^9/L pl,transfusion independence,no residual evidence of extramedullary leukemia;CR with incomplete blood count recovery:fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L or pl\<100\*10\^9/L;PR:all CR hematological values but ≥50% decrease in BM aspirate.Number of responders determined by independent review committee(IRC) assessment. |
| Duration of Complete Remission (CR) | From CR until first documentation of PD or relapse from CR or relapse after CR or PR (up to approximately 42 months) | Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML) or relapse after CR or PR (participants with HR MDS/CMML). Disease responses for HR MDS or CMML are based on the Modified IWG Response Criteria for MDS and for low-blast AML on the Revised IWG Response Criteria for AML. CR for HR MDS or CMML is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to \>=11 g/dL Hgb,\>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0\*10\^9/L and pl of \>=100\*10\^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (\<1.0\*10\^9/L) or thrombocytopenia (pl\<100\*10\^9/L). |
| Overall Survival (OS) | Up to approximately 6.9 years | Overall survival was defined as the time from randomization to death from any cause. |
| Duration of Overall Response (OR) | Up to approximately 42 months | Duration of OR: response to first documentation of PD or relapse from CR for low-blast AML or relapse after CR or PR for HR MDS/CMML. Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR+PR for HR MDS/CMML and CR+Cri+ PR for low-blast AML.CR for HR MDS/CMML:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11 g/dL Hgb,\>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood and PR:all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment but still \>5%. For low-blast AML-CR: morphologic leukemia-free state \>1.0\*10\^9 neutrophils,\>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with CRi: fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L or pl \<100\*10\^9/L; PR: all CR hematological values but \>=50% decrease in % of blasts in bone marrow aspirate. |
| Duration of Overall Response 2 (OR2) | Up to approximately 42 months | Duration of OR2: from date of first documentation of CR+PR+HI to first documentation of PD/relapse after CR/PR for responders of CR+PR+HI for HR MDS/CMML and CR,CRi,PR for low-blast AML. For HR MDS/CMML-CR:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11 g/dL Hgb, \>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment, still \>5%; HI:Hgb inc \>=1.5 g/dL if baseline \<11 g/dL; pl inc\>=30\*10\^9/L if baseline\>20\*10\^9/L or inc from\<20\*10\^9/L to\>20\*10\^9/L by at least 100%; neutrophil inc by 100% and absolute inc of \>0.5\*10\^9/L if baseline \<1.0\*10\^9/L.For low-blast AML-CR: morphologic leukemia-free state,\>1.0\*10\^9 neutrophils,\>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia;CRi: fulfill CR criteria except residual neutropenia\<1.0\*10\^9/L or pl \<100\*10\^9/L;PR:all CR hematological values but\>=50% decrease in bone marrow aspirate. |
| Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence | Up to approximately 42 months | 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. |
| Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence | Up to approximately 42 months | 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. |
| Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi) | From randomization until CR or PR (up to approximately 42 months) | Time to first CR or PR is defined as the time from randomization to first documented CR or PR, whichever occurs first. Disease responses for HR MDS or CMML or low-blast AML cycle 6 are based on Modified IWG Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. For HR MDS or CMML-CR:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11 g/dL Hgb,\>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment but still\>5%; For low-blast AML-CR: morphologic leukemia-free state,\>1.0\*10\^9/L neutrophils, pl\>=100\*10\^9/L, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery: fulfill CR criteria except residual neutropenia\<1.0\*10\^9/L or pl \<100\*10\^9/L; PR: all CR hematological values but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate. |
| Number of Participants With Hematologic Improvement (HI) | From randomization until HI (up to approximately 42 months) | 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. |
| Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML | From randomization until transformation to AML or until initiation of subsequent therapy (up to approximately 42 months) | 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%. |
| Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death | 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) | Time to PD, relapse after CR(low-blast AML), relapse after CR or PR(HR MDS/CMML), or death,defined as time from date of randomization until date of first documentation of PD,relapse after CR(low-blast AML),relapse after CR or PR(HR MDS/CMML),or death due to any cause, whichever occurs first. In HR MDS/CMML,PD: Participants with\<5% blasts:\>=50% inc \>5% blasts, with 5%-9% blasts:\>=50% inc\>10% blasts, with 10%-19% blasts:\>=50% inc \>20% blasts,with 20%-30% blasts, at least 50% decrement from maximum remission/response in granulocytes or pl or reduction in Hgb by\>=2 g/dL/new transfusion dependence.Relapse after CR or PR: return to pretreatment bone marrow blast %/Decrement of \>=50% from maximum remission/response levels in granulocytes/pl/reduction in Hgb conc.\>=1.5 g/dL/transfusion dependence. In AML,PD:\>50% inc in bone marrow blasts to \>30% blasts,\>50% inc in circulating blasts to\>30% blasts in peripheral blood, Development of extramedullary disease/new sites of extramedullary leukemia. |
| 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 | Baseline, at approximately 58 months | The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. Most of the 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QOL scale, higher scores represent better QOL; for the symptom scales, lower scores represent better QOL. The change from baseline at end of treatment is reported. |
| 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 | From randomization until CR, CRi and PR (up to approximately 42 months) | Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR + PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment but still\>5%. For low-blast AML-CR: morphologic leukemia-free state, \>1.0\*10\^9 neutrophils,\>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia\<1.0\*10\^9/L or pl\<100\*10\^9/L; PR: all CR hematological values but\>=50% decrease in the percentage of blasts to 5% to 25% in bone marrow aspirate. |
| Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group | From randomization until transformation to AML if eligible or death (up to approximately 42 months) | 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. |
| Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group | From randomization until death (up to approximately 42 months) | 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. |
| Number of Participants With Overall Response by Cycle 6 | Up to Cycle 6 (up to approximately Day 168) | Responses for HR MDS/CMML are based on Modified International Working Group (IWG) Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR and PR for HR MDS/CMML and CR+CR with incomplete blood count recovery(CRi)+PR for low-blast AML. CR for HR MDS/CMML:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11g/dL hemoglobin (Hgb),\>=100\*10\^9/L platelet (pl),\>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood, and PR:all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still \>5%. For low-blast AML-CR:morphologic leukemia-free state,\>1.0\*10\^9 neutrophils, \>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L/thrombocytopenia (pl\<100\*10\^9/L); PR:all CR hematological values but\>=50% decrease in percentage of blasts to 5%-25% in bone marrow aspirate. |
| Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi) | From CR until first documentation of PD or relapse from CR or relapse after CR or PR (up to approximately 42 months) | Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML). Disease responses for low-blast AML were based on the Revised IWG Response Criteria for AML. CR is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to \>=11 g/dL hemoglobin (Hgb),\>=100\*10\^9/liter (/L) platelets (pl),\>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0\*10\^9/L and pl of \>=100\*10\^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (\<1.0\*10\^9/L) or thrombocytopenia (pl\<100\*10\^9/L). |
Countries
Australia, Belgium, Brazil, Canada, China, Czechia, France, Germany, Greece, Israel, Italy, Japan, Mexico, Poland, Russia, South Korea, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 130 investigative sites globally from 28 November 2017 to 14 October 2024.
Pre-assignment 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.
Participants by arm
| Arm | Count |
|---|---|
| Azacitidine 75 mg/m^2 Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles. | 227 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 Participants were administered azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to a maximum of 63 cycles. | 227 |
| Total | 454 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Reason Not Specified | 3 | 8 |
| Overall Study | Withdrawal by Subject | 27 | 17 |
Baseline characteristics
| Characteristic | Azacitidine 75 mg/m^2 | Total | Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 |
|---|---|---|---|
| Age, Continuous | 73.0 years STANDARD_DEVIATION 8.22 | 73 years STANDARD_DEVIATION 7.93 | 73.0 years STANDARD_DEVIATION 7.65 |
| Body Surface Area | 1.89 meter square (m^2) STANDARD_DEVIATION 0.228 | 1.88 meter square (m^2) STANDARD_DEVIATION 0.231 | 1.86 meter square (m^2) STANDARD_DEVIATION 0.233 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 57 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 188 Participants | 377 Participants | 189 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 20 Participants | 7 Participants |
| Height | 167.59 centimeter (cm) STANDARD_DEVIATION 9.439 | 166.95 centimeter (cm) STANDARD_DEVIATION 9.783 | 166.31 centimeter (cm) STANDARD_DEVIATION 10.098 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 20 Participants | 51 Participants | 31 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 25 Participants | 10 Participants |
| Race (NIH/OMB) White | 189 Participants | 369 Participants | 180 Participants |
| Region of Enrollment Australia | 3 Participants | 7 Participants | 4 Participants |
| Region of Enrollment Belgium | 8 Participants | 11 Participants | 3 Participants |
| Region of Enrollment Brazil | 10 Participants | 28 Participants | 18 Participants |
| Region of Enrollment Canada | 2 Participants | 9 Participants | 7 Participants |
| Region of Enrollment China | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Czech Republic | 10 Participants | 16 Participants | 6 Participants |
| Region of Enrollment France | 13 Participants | 21 Participants | 8 Participants |
| Region of Enrollment Germany | 6 Participants | 9 Participants | 3 Participants |
| Region of Enrollment Greece | 30 Participants | 58 Participants | 28 Participants |
| Region of Enrollment Israel | 6 Participants | 12 Participants | 6 Participants |
| Region of Enrollment Italy | 14 Participants | 23 Participants | 9 Participants |
| Region of Enrollment Japan | 12 Participants | 38 Participants | 26 Participants |
| Region of Enrollment Korea, Republic of | 4 Participants | 6 Participants | 2 Participants |
| Region of Enrollment Mexico | 2 Participants | 7 Participants | 5 Participants |
| Region of Enrollment Poland | 11 Participants | 21 Participants | 10 Participants |
| Region of Enrollment Russia | 22 Participants | 34 Participants | 12 Participants |
| Region of Enrollment Spain | 26 Participants | 49 Participants | 23 Participants |
| Region of Enrollment Turkey | 5 Participants | 10 Participants | 5 Participants |
| Region of Enrollment United Kingdom | 1 Participants | 4 Participants | 3 Participants |
| Region of Enrollment United States of America | 40 Participants | 89 Participants | 49 Participants |
| Sex: Female, Male Female | 85 Participants | 180 Participants | 95 Participants |
| Sex: Female, Male Male | 142 Participants | 274 Participants | 132 Participants |
| Weight | 77.65 kilogram (kg) STANDARD_DEVIATION 16.143 | 76.73 kilogram (kg) STANDARD_DEVIATION 16.078 | 75.82 kilogram (kg) STANDARD_DEVIATION 15.996 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 153 / 220 | 150 / 223 |
| other Total, other adverse events | 207 / 220 | 210 / 223 |
| serious Total, serious adverse events | 145 / 220 | 156 / 223 |
Outcome results
Primary
Event-Free Survival (EFS)
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.
Time frame: From randomization until transformation to acute myeloid leukemia, or death due to any cause: up to approximately 42 months
Population: ITT Population included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Event-Free Survival (EFS) | 15.7 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Event-Free Survival (EFS) | 17.7 months |
Comparison: IPSS-R indicates the Revised International Prognostic Scoring System.p-value: =0.55795% CI: [0.757, 1.238]Log Rank
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
The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. Most of the 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QOL scale, higher scores represent better QOL; for the symptom scales, lower scores represent better QOL. The change from baseline at end of treatment is reported.
Time frame: Baseline, at approximately 58 months
Population: ITT Population included all participants who were randomized. All participants with PRO measurements at baseline and with data available at end of treatment were analyzed for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Emotional Functioning Score: Baseline | 76.0 score on a scale | Standard Deviation 20.96 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Financial Difficulties Score: Change from Baseline | 5.9 score on a scale | Standard Deviation 27.03 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Nausea/Vomiting Score: Change from Baseline | 2.4 score on a scale | Standard Deviation 19.08 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Emotional Functioning Score: Change from Baselline | -2.5 score on a scale | Standard Deviation 23.8 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Pain Score: Baseline | 20.9 score on a scale | Standard Deviation 25.55 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Physical Functioning Score: Change from Baseline | -7.5 score on a scale | Standard Deviation 22.82 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Pain Score: Change from Baseline | 5.8 score on a scale | Standard Deviation 30.36 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Cognitive Functioning Score: Baseline | 84.6 score on a scale | Standard Deviation 18.29 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Dyspnoea Score: Baseline | 25.4 score on a scale | Standard Deviation 29.83 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Global Health Status/QoL Score: Change from Baseline | -3.0 score on a scale | Standard Deviation 25.93 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Dyspnoea Score: Change from Baseline | 5.9 score on a scale | Standard Deviation 28.95 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Cognitive Functioning Score: Change from Baseline | -7.2 score on a scale | Standard Deviation 22.65 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Insomnia Score: Baseline | 27.2 score on a scale | Standard Deviation 27.96 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Role Functioning Score: Baseline | 66.9 score on a scale | Standard Deviation 30.88 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Insomnia Score: Change from Baseline | 3.2 score on a scale | Standard Deviation 34.32 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Appetite Loss Score: Baseline | 23.4 score on a scale | Standard Deviation 29.29 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Social Functioning Score: Baseline | 79.3 score on a scale | Standard Deviation 25.37 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Appetite Loss Score: Change from Baseline | 4.6 score on a scale | Standard Deviation 38.68 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Constipation Score: Baseline | 14.7 score on a scale | Standard Deviation 24.78 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Global Health Status/QoL Score: Baseline | 60.3 score on a scale | Standard Deviation 22.11 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Constipation Score: Change from Baseline | 5.5 score on a scale | Standard Deviation 29.56 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Social Functioning Score: Change from Baseline | -13.7 score on a scale | Standard Deviation 33.89 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Diarrhoea Score: Baseline | 7.6 score on a scale | Standard Deviation 18.84 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Role Functioning Score: Change from Baseline | -11.8 score on a scale | Standard Deviation 35.41 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Diarrhoea Score: Change from Baseline | 3.0 score on a scale | Standard Deviation 22.8 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Fatigue Score: Baseline | 38.5 score on a scale | Standard Deviation 25.44 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Financial Difficulties Score: Baseline | 14.2 score on a scale | Standard Deviation 25.37 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Physical Functioning Score: Baseline | 69.4 score on a scale | Standard Deviation 22.63 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | QLQ-C30 Summary Score: Baseline | 77.9 score on a scale | Standard Deviation 14.9 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Fatigue Score: Change from Baseline | 6.6 score on a scale | Standard Deviation 26.41 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | QLQ-C30 Summary Score: Change from Baseline | -6.1 score on a scale | Standard Deviation 18.84 |
| Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Nausea/Vomiting Score: Baseline | 4.6 score on a scale | Standard Deviation 11.39 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | QLQ-C30 Summary Score: Change from Baseline | -8.6 score on a scale | Standard Deviation 17.75 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Insomnia Score: Change from Baseline | 4.6 score on a scale | Standard Deviation 34.09 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Appetite Loss Score: Change from Baseline | 16.0 score on a scale | Standard Deviation 34.03 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Financial Difficulties Score: Baseline | 18.4 score on a scale | Standard Deviation 26.76 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Global Health Status/QoL Score: Baseline | 61.6 score on a scale | Standard Deviation 21.13 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Global Health Status/QoL Score: Change from Baseline | -8.4 score on a scale | Standard Deviation 26.89 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Physical Functioning Score: Baseline | 75.7 score on a scale | Standard Deviation 20.38 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Physical Functioning Score: Change from Baseline | -13.4 score on a scale | Standard Deviation 27.51 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Role Functioning Score: Baseline | 73.7 score on a scale | Standard Deviation 28.55 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Role Functioning Score: Change from Baseline | -18.3 score on a scale | Standard Deviation 36.72 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Emotional Functioning Score: Baseline | 77.6 score on a scale | Standard Deviation 22.1 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Emotional Functioning Score: Change from Baselline | -5.9 score on a scale | Standard Deviation 22.41 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Cognitive Functioning Score: Baseline | 86.1 score on a scale | Standard Deviation 17.6 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Cognitive Functioning Score: Change from Baseline | -10.4 score on a scale | Standard Deviation 24.38 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Social Functioning Score: Baseline | 78.8 score on a scale | Standard Deviation 25.82 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Social Functioning Score: Change from Baseline | -16.5 score on a scale | Standard Deviation 34.78 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Fatigue Score: Baseline | 33.8 score on a scale | Standard Deviation 24.24 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Fatigue Score: Change from Baseline | 12.3 score on a scale | Standard Deviation 31.22 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Nausea/Vomiting Score: Baseline | 4.7 score on a scale | Standard Deviation 10.96 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Nausea/Vomiting Score: Change from Baseline | 1.9 score on a scale | Standard Deviation 15 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Pain Score: Baseline | 19.4 score on a scale | Standard Deviation 26.42 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Pain Score: Change from Baseline | 6.8 score on a scale | Standard Deviation 33.34 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Dyspnoea Score: Baseline | 24.4 score on a scale | Standard Deviation 28.9 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Dyspnoea Score: Change from Baseline | 5.9 score on a scale | Standard Deviation 29.46 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Insomnia Score: Baseline | 25.7 score on a scale | Standard Deviation 30.68 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Appetite Loss Score: Baseline | 15.6 score on a scale | Standard Deviation 23.99 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Constipation Score: Baseline | 13.8 score on a scale | Standard Deviation 22.47 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Constipation Score: Change from Baseline | 5.1 score on a scale | Standard Deviation 28.42 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Diarrhoea Score: Baseline | 7.0 score on a scale | Standard Deviation 16.75 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Diarrhoea Score: Change from Baseline | 1.9 score on a scale | Standard Deviation 27.65 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | Financial Difficulties Score: Change from Baseline | 7.4 score on a scale | Standard Deviation 30.46 |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Change From Baseline in Health-Related Quality of Life (HRQOL) Using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 | QLQ-C30 Summary Score: Baseline | 80.5 score on a scale | Standard Deviation 15.08 |
Secondary
Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi)
Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML). Disease responses for low-blast AML were based on the Revised IWG Response Criteria for AML. CR is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to \>=11 g/dL hemoglobin (Hgb),\>=100\*10\^9/liter (/L) platelets (pl),\>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0\*10\^9/L and pl of \>=100\*10\^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (\<1.0\*10\^9/L) or thrombocytopenia (pl\<100\*10\^9/L).
Time frame: From CR until first documentation of PD or relapse from CR or relapse after CR or PR (up to approximately 42 months)
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for participants with CR and CRi.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi) | 8.5 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi) | 15.0 months |
Comparison: Duration of Complete Remission + Complete Remission with Incomplete Blood Count Recovery (CRi)p-value: =0.37395% CI: [0.306, 2.339]Log Rank
Secondary
Duration of Complete Remission (CR)
Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML) or relapse after CR or PR (participants with HR MDS/CMML). Disease responses for HR MDS or CMML are based on the Modified IWG Response Criteria for MDS and for low-blast AML on the Revised IWG Response Criteria for AML. CR for HR MDS or CMML is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to \>=11 g/dL Hgb,\>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0\*10\^9/L and pl of \>=100\*10\^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (\<1.0\*10\^9/L) or thrombocytopenia (pl\<100\*10\^9/L).
Time frame: From CR until first documentation of PD or relapse from CR or relapse after CR or PR (up to approximately 42 months)
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for participants with complete remission.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Duration of Complete Remission (CR) | 13.1 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Duration of Complete Remission (CR) | 17.2 months |
Comparison: Duration of CRp-value: =0.07295% CI: [0.402, 1.146]Log Rank
Secondary
Duration of Overall Response 2 (OR2)
Duration of OR2: from date of first documentation of CR+PR+HI to first documentation of PD/relapse after CR/PR for responders of CR+PR+HI for HR MDS/CMML and CR,CRi,PR for low-blast AML. For HR MDS/CMML-CR:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11 g/dL Hgb, \>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment, still \>5%; HI:Hgb inc \>=1.5 g/dL if baseline \<11 g/dL; pl inc\>=30\*10\^9/L if baseline\>20\*10\^9/L or inc from\<20\*10\^9/L to\>20\*10\^9/L by at least 100%; neutrophil inc by 100% and absolute inc of \>0.5\*10\^9/L if baseline \<1.0\*10\^9/L.For low-blast AML-CR: morphologic leukemia-free state,\>1.0\*10\^9 neutrophils,\>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia;CRi: fulfill CR criteria except residual neutropenia\<1.0\*10\^9/L or pl \<100\*10\^9/L;PR:all CR hematological values but\>=50% decrease in bone marrow aspirate.
Time frame: Up to approximately 42 months
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Three participants who were non-responders (for OR2) as per the IRC were included in this outcome measure as they had assessment of HI and duration of OR2 for these participants could still be derived based on the pre-specified criteria for HR MDS/CMML participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Duration of Overall Response 2 (OR2) | 18.3 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Duration of Overall Response 2 (OR2) | 18.9 months |
Comparison: Duration of Overall Response 2 (OR2)p-value: =0.15195% CI: [0.514, 1.231]Log Rank
Secondary
Duration of Overall Response (OR)
Duration of OR: response to first documentation of PD or relapse from CR for low-blast AML or relapse after CR or PR for HR MDS/CMML. Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR+PR for HR MDS/CMML and CR+Cri+ PR for low-blast AML.CR for HR MDS/CMML:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11 g/dL Hgb,\>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood and PR:all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment but still \>5%. For low-blast AML-CR: morphologic leukemia-free state \>1.0\*10\^9 neutrophils,\>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with CRi: fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L or pl \<100\*10\^9/L; PR: all CR hematological values but \>=50% decrease in % of blasts in bone marrow aspirate.
Time frame: Up to approximately 42 months
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Duration of Overall Response (OR) | 18.3 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Duration of Overall Response (OR) | 17.1 months |
Comparison: Duration of Overall Response (OR)p-value: =0.3295% CI: [0.542, 1.458]Log Rank
Secondary
Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence
Duration of RBC 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.
Time frame: Up to approximately 42 months
Population: ITT Population included all participants who were randomized. Number analyzed is the number of participants who achieved transfusion independence for the specified category, with data available for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Azacitidine 75 mg/m^2 | Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence | Duration of RBC Transfusion Independence | 15.6 months |
| Azacitidine 75 mg/m^2 | Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence | Duration of Platelet Transfusion Independence | 14.9 months |
| Azacitidine 75 mg/m^2 | Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence | Duration of Transfusion Independence | 12.0 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence | Duration of Transfusion Independence | 13.5 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence | Duration of RBC Transfusion Independence | 13.5 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Duration of Red Blood Cells (RBCs) and Duration of Platelet-transfusion Independence and Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence | Duration of Platelet Transfusion Independence | 11.6 months |
Comparison: Duration of RBC Transfusion Independencep-value: =0.77495% CI: [0.715, 2.119]Log Rank
Comparison: Duration of Platelet Transfusion Independencep-value: =0.80195% CI: [0.567, 4.147]Log Rank
Comparison: Duration of Transfusion Independencep-value: =0.4595% CI: [0.58, 1.614]Log Rank
Secondary
Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group
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.
Time frame: From randomization until transformation to AML if eligible or death (up to approximately 42 months)
Population: ITT Population included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group | 12.8 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Event-Free Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group | 14.6 months |
Comparison: Event-Free Survival in Participants who have TP53 Mutations, 17p Deletions, and/or are Determined to be in an Adverse Cytogenetic Risk Groupp-value: =0.2495% CI: [0.608, 1.263]Log Rank
Secondary
Kaplan-Meier Estimates of One-Year Survival Rate
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.
Time frame: Year 1
Population: ITT Population included all participants who were randomized. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Kaplan-Meier Estimates of One-Year Survival Rate | 0.693 percentage probability |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Kaplan-Meier Estimates of One-Year Survival Rate | 0.646 percentage probability |
Secondary
Kaplan-Meier Estimates of Six-Month Survival Rate
Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of Month 6 from randomization are presented.
Time frame: Month 6
Population: ITT Population included all participants who were randomized. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Kaplan-Meier Estimates of Six-Month Survival Rate | 0.825 percentage probability |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Kaplan-Meier Estimates of Six-Month Survival Rate | 0.810 percentage probability |
Secondary
Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML
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%.
Time frame: From randomization until transformation to AML or until initiation of subsequent therapy (up to approximately 42 months)
Population: ITT Population included all participants who were randomized.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML | 3 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML | 9 Participants |
Comparison: Number of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML95% CI: [-0.3, 5.58]
Secondary
Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi)
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).
Time frame: From randomization until CR (up to approximately 42 months)
Population: Response-Evaluable Population (REP) included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi) | 71 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi) | 63 Participants |
Comparison: Number of Participants With Complete Remission (CR) and CR+Complete Remission with Incomplete Blood Count Recovery (CRi)p-value: =0.37495% CI: [-13.18, 4.83]Cochran-Mantel-Haenszel
Secondary
Number of Participants With CR and Marrow CR
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.
Time frame: From randomization until CR or marrow CR (up to approximately 42 months)
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With CR and Marrow CR | 91 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With CR and Marrow CR | 87 Participants |
Secondary
Number of Participants With CR and Marrow CR and PR
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%.
Time frame: From randomization until CR or Marrow CR and PR (up to approximately 42 months)
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With CR and Marrow CR and PR | 91 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With CR and Marrow CR and PR | 87 Participants |
Secondary
Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI)
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.
Time frame: From randomization until CR, marrow CR, PR or HI (up to approximately 42 months)
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI) | 112 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI) | 117 Participants |
Secondary
Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI)
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.
Time frame: From randomization until, CR, PR or HI (up to approximately 42 months)
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI) | 77 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI) | 76 Participants |
Secondary
Number of Participants With Hematologic Improvement (HI)
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.
Time frame: From randomization until HI (up to approximately 42 months)
Population: REP included all participants who received at least 1 dose of study drug and had a baseline and at least 1 postbaseline disease assessment. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With Hematologic Improvement (HI) | 76 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With Hematologic Improvement (HI) | 70 Participants |
Comparison: Number of Participants With HIp-value: =0.3295% CI: [-16.36, 5.44]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Overall Response 2 (OR2)
OR2=participant with best overall response of CR+PR+HI in HR MDS/CMML participants,or of CR+CRi+PR in low-blast AML participants.CR:≤5% myeloblasts with normal maturation of all bone marrow(BM)cell lines,≥11g/dL Hgb,≥100\*10\^9/L pl,≥1.0\*10\^9/L neutrophils,0% blasts in peripheral blood;PR:all CR criteria met except BM blasts ≥50% decrease over pretreatment but still \>5%;HI:Hgb increase(inc) ≥1.5g/dL if baseline(BL)\<11 g/dL;pl inc≥30\*10\^9/L if BL\>20\*10\^9/L or inc from \<20\*10\^9/L to \>20\*10\^9/L and by 100%;neutrophil inc by 100%;absolute inc of \>0.5\*10\^9/L if BL\<100\*10\^9/L.For low-blast AML-CR:morphologic leukemia-free state \>1.0\*10\^9 neutrophils,≥100\*10\^9/L pl,transfusion independence,no residual evidence of extramedullary leukemia;CR with incomplete blood count recovery:fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L or pl\<100\*10\^9/L;PR:all CR hematological values but ≥50% decrease in BM aspirate.Number of responders determined by independent review committee(IRC) assessment.
Time frame: From randomization until, CR, PR or HI or CR, CRi or PR (up to approximately 42 months)
Population: REP: all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for responders. Three participants were not counted as responders for OR2 as the IRC assessed these participants as non-responders.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With Overall Response 2 (OR2) | 94 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With Overall Response 2 (OR2) | 94 Participants |
Comparison: Number of Participants with OR2p-value: =0.89195% CI: [-10.03, 9.15]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Overall Response by Cycle 6
Responses for HR MDS/CMML are based on Modified International Working Group (IWG) Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR and PR for HR MDS/CMML and CR+CR with incomplete blood count recovery(CRi)+PR for low-blast AML. CR for HR MDS/CMML:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11g/dL hemoglobin (Hgb),\>=100\*10\^9/L platelet (pl),\>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood, and PR:all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still \>5%. For low-blast AML-CR:morphologic leukemia-free state,\>1.0\*10\^9 neutrophils, \>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L/thrombocytopenia (pl\<100\*10\^9/L); PR:all CR hematological values but\>=50% decrease in percentage of blasts to 5%-25% in bone marrow aspirate.
Time frame: Up to Cycle 6 (up to approximately Day 168)
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 post-baseline disease assessment. Number analyzed is the number of participants with data available for analysis for the specified category.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With Overall Response by Cycle 6 | Overall Response for HR MDS/CMML | 36 Participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Overall Response by Cycle 6 | Overall Response for Low-blast AML | 13 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With Overall Response by Cycle 6 | Overall Response for HR MDS/CMML | 29 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With Overall Response by Cycle 6 | Overall Response for Low-blast AML | 22 Participants |
Comparison: Overall Response for HR MDS/CMMLp-value: =0.26195% CI: [-13.95, 3.68]Cochran-Mantel-Haenszel
Comparison: Overall Response for Low-blast AMLp-value: =0.02695% CI: [3.22, 41.49]Cochran-Mantel-Haenszel
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
Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR + PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment but still\>5%. For low-blast AML-CR: morphologic leukemia-free state, \>1.0\*10\^9 neutrophils,\>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia\<1.0\*10\^9/L or pl\<100\*10\^9/L; PR: all CR hematological values but\>=50% decrease in the percentage of blasts to 5% to 25% in bone marrow aspirate.
Time frame: From randomization until CR, CRi and PR (up to approximately 42 months)
Population: ITT Population included all participants who were randomized. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis for the specified category.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With Overall Response in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group | OR: HR MDS/CMML Participants | 14 Participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Overall Response in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group | OR: Low-blast AML Participants | 13 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With Overall Response in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group | OR: HR MDS/CMML Participants | 13 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With Overall Response in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group | OR: Low-blast AML Participants | 12 Participants |
Comparison: OR: HR MDS/CMML Participantsp-value: =0.68395% CI: [-19.44, 13.75]Cochran-Mantel-Haenszel
Comparison: ORR: Low-blast AML Participantsp-value: =0.8495% CI: [-20.39, 25.12]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Overall Response (OR)
Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR or PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still\>5%. For low-blast AML-CR:morphologic leukemia-free state\>1.0\*10\^9 neutrophils, \>=100\*10\^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia \<1.0\*10\^9/L or pl \<100\*10\^9/L; PR: all CR hematological values but \>=50% decrease in bone marrow aspirate.
Time frame: From randomization until CR and PR or CR, CRi and PR (up to approximately 42 months)
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Number of Participants With Overall Response (OR) | 73 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Number of Participants With Overall Response (OR) | 64 Participants |
Comparison: Number of Participants with ORp-value: =0.32995% CI: [-13.72, 4.39]Cochran-Mantel-Haenszel
Secondary
Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group
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.
Time frame: From randomization until death (up to approximately 42 months)
Population: ITT Population included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group | 12.8 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Overall Survival in Participants Who Have TP53 Mutations, 17p Deletions, and/or Are Determined to be in an Adverse Cytogenetic Risk Group | 16.1 months |
Comparison: Overall Survival in Participants who have TP53 Mutations, 17p Deletions, and/or are Determined to be in an Adverse Cytogenetic Risk Groupp-value: =0.14595% CI: [0.58, 1.178]Log Rank
Secondary
Overall Survival (OS)
Overall survival was defined as the time from randomization to death from any cause.
Time frame: Up to approximately 6.9 years
Population: ITT Population included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Overall Survival (OS) | 16.8 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Overall Survival (OS) | 20.3 months |
Comparison: Overall Survival (OS)p-value: =0.15295% CI: [0.709, 1.113]Log Rank
Secondary
Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence
A participant was defined as RBC or platelet-transfusion independent if he/she received no RBC or platelet transfusions for a period of at least 8 weeks before the first dose of study drug through 30 days after the last dose of any study drug. Rate of transfusion independence was defined as number of participants who became transfusion independent divided by the number of participants who were transfusion dependent at Baseline.
Time frame: Up to approximately 42 months
Population: ITT Population included all participants who were randomized. Overall number analyzed is the number of participants from a subset of the ITT Population who were transfusion dependent at Baseline. Number analyzed is the number of participants who were transfusion dependent at Baseline for the specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine 75 mg/m^2 | Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence | Percentage of Participants With RBCs-transfusion Independence | 44.3 percentage of participants |
| Azacitidine 75 mg/m^2 | Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence | Percentage of Participants With Platelet-transfusion Independence | 48.9 percentage of participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence | Percentage of Participants With RBCs-transfusion Independence | 47.5 percentage of participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence | Percentage of Participants With Platelet-transfusion Independence | 45.5 percentage of participants |
Comparison: Percentage of Participants With RBC-transfusion Independencep-value: =0.57395% CI: [-9.02, 15.55]Cochran-Mantel-Haenszel
Comparison: Percentage of Participants With Platelet-transfusion Independencep-value: =0.47795% CI: [-25.84, 18.97]Cochran-Mantel-Haenszel
Secondary
Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60
60-day mortality was defined as number of participants who died within 60 days from the first dose of study drug.
Time frame: Up to Day 60
Population: Safety Population included all enrolled participants who received at least 1 dose of azacitidine alone or pevonedistat + azacitidine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60 | 15 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60 | 14 Participants |
Secondary
Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30
30-day mortality was defined as number of participants who died within 30 days from the first dose of study drug.
Time frame: Up to Day 30
Population: Safety Population included all enrolled participants who received at least 1 dose of azacitidine alone or pevonedistat + azacitidine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30 | 6 Participants |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30 | 5 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
Time to AML transformation in HR MDS and CMML participants was defined as time from randomization to documented AML transformation as determined by the independent review committee (IRC) assessment. Participants who died before progression to AML were censored. Transformation to AML was defined, according to WHO classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%.
Time frame: From randomization until transformation to AML (up to approximately 42 months)
Population: ITT Population included all participants who were randomized. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis for the given category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Azacitidine 75 mg/m^2 | Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants | HR MDS Participants | 35.6 months |
| Azacitidine 75 mg/m^2 | Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants | HR CMML Participants | NA months |
| Azacitidine 75 mg/m^2 | Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants | HR MDS/CMML Participants | 35.6 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants | HR MDS Participants | NA months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants | HR CMML Participants | NA months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants | HR MDS/CMML Participants | NA months |
Comparison: Time to AML Transformation in HR MDS Participantsp-value: =0.56295% CI: [0.66, 1.63]Log Rank
Comparison: Time to AML Transformation in HR CMML Participantsp-value: =0.60395% CI: [0.068, 33.773]Log Rank
Comparison: Time to AML Transformation in HR MDS/CMML Participantsp-value: =0.55895% CI: [0.663, 1.61]Log Rank
Secondary
Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi)
Time to first CR or PR is defined as the time from randomization to first documented CR or PR, whichever occurs first. Disease responses for HR MDS or CMML or low-blast AML cycle 6 are based on Modified IWG Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. For HR MDS or CMML-CR:\<=5% myeloblasts with normal maturation of all bone marrow cell lines,\>=11 g/dL Hgb,\>=100\*10\^9/L pl,\>=1.0\*10\^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts\>=50% decrease over pretreatment but still\>5%; For low-blast AML-CR: morphologic leukemia-free state,\>1.0\*10\^9/L neutrophils, pl\>=100\*10\^9/L, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery: fulfill CR criteria except residual neutropenia\<1.0\*10\^9/L or pl \<100\*10\^9/L; PR: all CR hematological values but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate.
Time frame: From randomization until CR or PR (up to approximately 42 months)
Population: REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi) | NA months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission With Incomplete Blood Count Recovery (CRi) | NA months |
Comparison: Time to First Complete Remission (CR) or Partial Remission (PR) or Complete Remission with Incomplete Blood Count Recovery (CRi)p-value: =0.22895% CI: [0.628, 1.234]Log Rank
Secondary
Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death
Time to PD, relapse after CR(low-blast AML), relapse after CR or PR(HR MDS/CMML), or death,defined as time from date of randomization until date of first documentation of PD,relapse after CR(low-blast AML),relapse after CR or PR(HR MDS/CMML),or death due to any cause, whichever occurs first. In HR MDS/CMML,PD: Participants with\<5% blasts:\>=50% inc \>5% blasts, with 5%-9% blasts:\>=50% inc\>10% blasts, with 10%-19% blasts:\>=50% inc \>20% blasts,with 20%-30% blasts, at least 50% decrement from maximum remission/response in granulocytes or pl or reduction in Hgb by\>=2 g/dL/new transfusion dependence.Relapse after CR or PR: return to pretreatment bone marrow blast %/Decrement of \>=50% from maximum remission/response levels in granulocytes/pl/reduction in Hgb conc.\>=1.5 g/dL/transfusion dependence. In AML,PD:\>50% inc in bone marrow blasts to \>30% blasts,\>50% inc in circulating blasts to\>30% blasts in peripheral blood, Development of extramedullary disease/new sites of extramedullary leukemia.
Time frame: From randomization until PD, relapse after CR, or relapse after CR or PR, or death due to any cause, whichever occurs first (up to approximately 42 months)
Population: ITT Population included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 75 mg/m^2 | Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death | 11.8 months |
| Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Time to Progressive Disease (PD), Relapse After CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Death | 13.1 months |
Comparison: Time to Progressive Disease (PD), Relapse after CR (Low-blast AML), Relapse After CR or PR (HR MDS/CMML), or Deathp-value: =0.08495% CI: [0.689, 1.067]Log Rank