Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myelogenous Leukemia
Conditions
Interventions
investigational material(s)
Generic name etc : Azacitidine + Pevonedistat
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Inves
Sponsors
Takeda Pharmaceutical Company Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or nonproliferative chronic myelomonocytic leukemia (CMML) (i.e., with white blood cell [WBC] 6 points). - High (>4.5-6 points). - Intermediate (>3-4.5 points): a patient 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) performance 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 =71 years). - + 0 for (PS=0), +2 for (PS=1), +4 for (PS >1). - + 0 for (platelets =50).
Exclusion criteria
Exclusion criteria: 1. HR MDS 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 x 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 |
|---|---|
| Event-Free Survival (EFS) Time Frame: From randomization until transformation to acute myeloid leukemia, or death due to any cause up to data cut-off date: 28 May 2021 (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 occured 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 |
|---|---|
| 1.Efficacy; Overall Survival (OS) Time Frame: From randomization until death OS is calculated as the time from date of randomization to the date of death due to any cause. 2.Efficacy; Six-Month Survival Rate Time Frame: Up to Month 6 3.Efficacy; One-Year Survival Rate Time Frame: Up to Year 1 4.Efficacy; Thirty-Day Mortality Rate Time Frame: Up to Day 30 5.Efficacy; Sixty-Day Mortality Rate Time Frame: Up to Day 60 6.Efficacy; Time to AML Transformation in HR MDS, HR CMML and HR MDS/CMML Participants Time Frame: From randomization until transformation to AML 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. 7.Efficacy; Percentage of Participants with Complete Remission (CR) and CR+Complete Remission with Incomplete Blood Count Recovery (CRi) Time Frame: From randomization until CR 8.Efficacy; Percentage of Participants with CR and Marrow CR Time Frame: From randomization until CR or marrow CR 9.Efficacy; Percentage of Participants with CR, Partial Remission (PR) and Hematologic Improvement (HI) Time Frame: From randomization until, CR, PR or HI 10.Efficacy; Percentage of Participants with CR and Marrow CR and PR Time Frame: From randomization until CR or Marrow CR and PR 11.Efficacy; Percentage of Participants with CR and Marrow CR, PR and HI Time Frame: From randomization until CR, marrow CR, PR or HI 12.Efficacy; Percentage of Participants with Overall Response Rate (ORR) Time Frame: From randomization until CR and PR or CR, CRi and PR Overall response=CR or PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. 13.Efficacy; Percentage of Participants with Overall Response 2 (OR2) Time Frame: From randomization until, CR, PR or HI or CR, CRi or PR OR2=CR, PR or HI for HR MDS/CMML and CR, CRi or PR for low-blast AML. 14.Efficacy; Duration of CR Time Frame: From CR until first documentation of PD or relap | — |
Countries
Australia, Belgium, Brazil, Canada, China, Czechia, France, Germany, Greece, Israel, Italy, Japan, Korea, Mexico, Poland, Russian, Spain, Turkey, United Kingdom, United States
Outcome results
None listed