Higher-Risk Myelodysplastic Syndromes (MDS) Chronic Myelomonocytic Leukemia (CMML) Low-Blast Acute Myelogenous Leukemia (AML) MedDRA version: 21.0 Level: LLT Classification code 10054350 Term: Chronic myelomonocytic leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: LLT Classification code 10024348 Term: Leukemia myelogenous System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cys
Conditions
Sponsors
Millennium Pharmaceuticals, Inc. (Takeda)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Male or female patients 18 years or older. 2.Morphologically confirmed diagnosis of MDS or nonproliferative CMML (ie, with WBC 6 points), - High (>4.5 – 6 points), or - 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. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 5. Patients with AML (20%-30% blasts) must have a 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 1). - + 0 for (platelets <50), +1 for (platelets =50). 6. Female patients who: - Are postmenopausal for at least 1 year before the Screening visit, OR - Are surgically sterile, OR - If they are of childbearing potential, agree to practice one highly effective method of contraception and one additional effective (barrier) method, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, OR - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) Male patients, even if surgically sterilized (ie, status postvasectomy), who: - Agree to practice effective barrier contraception during the entire study treatment period and through 120 days (or if the drug has a very long half-life, for 90 days plus five half-lives) after the last dose of study drug, or - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods
Exclusion criteria
Exclusion criteria: 1. Previous treatment for HR MDS or CMML or low-blast AML with chemotherapy or other antineoplastic agents including 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. 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. Patients with AML with a WBC count >50,000/ µL. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria 4. Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a patient 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 (eg, patients with AML with 20%-30% blasts and TRM =4). - Physician decision (eg, lack of available stem cell donor). The reason a patient is not eligible should be documented in the electronic case report form (eCRF). 5. Patients with either clinical evidence of or history of central nervous system involvement by AML. 6. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of study procedures or could limit expected patient survival to less than 6 months. 7. Treatment with any investigational products or participation in any interventional studies within 14 days before the first dose of any study drug. 8. Known hypersensitivity to pevonedistat or its excipients. 9. Known hypersensitivity to azacitidine or its excipients. 10. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. 11. Major surgery within 14 days before first dose or a scheduled surgery during study period; insertion of a venous access device (eg, catheter, port) is not considered major surgery. 12. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection. 13. Life-threatening illness unrelated to cancer. 14. Prothrombin time (PT) or aPTT >1.5×ULN or active uncontrolled coagulopathy or bleeding disorder. Patients therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment. 15. Known human immunodeficiency virus (HIV) seropositive. 16. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Patients who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. 17. Known hepatic cirrhosis or severe preexisting hepatic impairment. 18. 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 hyperte
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine whether the combination of pevonedistat and azacitidine improves event-free survival (EFS), when compared with single-agent azacitidine. (An event is defined as death or transformation to acute myeloid leukemia (AML) in patients with MDS or CMML, whichever occurs first, and is defined as death in patients with low-blast AML.) ;Secondary Objective: To determine whether the combination of pevonedistat and azacitidine improves overall survival (OS) when compared to single-agent azacitidine. To determine in patients with HR MDS,patients with HR CMML, and patients with HR MDS/CMML whether the combination of pevonedistat and azacitidine delays time to AML transformation when compared tosingle-agent azacitidine. (Please refer to protocol for detailed list);Primary end point(s): - EFS: time from randomization to the date of an EFS event (defined as death or transformation to AML in patients with MDS or CMML, whichever occurs first, and defined as death in patients with low-blast AML).;Timepoint(s) of evaluation of this end point: - EFS is defined as the time from randomization to the occurrence of an event. - ORR by cycle 6 (28 day cycles). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - OS. - 6-month and 1-year survival rates. - Time to AML transformation in patients with HR MDS, patients with HR CMML, and patients with HR MDS/CMML. - Rate of CR (CR in patients with HR MDS or CMML, CR+CRi in patients with low-blast AML), CR+marrow CR (in patients with HR MDS or CMML), CR+PR+HI (in patients with HR MDS or CMML), CR+marrow CR+PR (in patients with HR MDS or CMML), CR+marrow CR+PR+HI (in patients with HR MDS or CMML), overall response, and overall response 2. Overall response in patients with HR MDS or CMML is defined as CR+PR; overall response in patients with low-blast AML is defined as CR+CRi+PR. Overall response 2 in patients with HR MDS or CMML is defined as CR+PR+HI; overall response 2 in patients with low-blast AML is defined as CR+CRi+PR. - Duration of CR (CR for HR MDS or CMML, CR+CRi for low-blast AML), overall response (CR+PR for HR MDS or CMML, CR+CRi+PR for low-blast AML), and overall response 2 (CR+PR+HI for HR MDS or CMML, CR+CRi+PR for low-blast AML). - Rates of RBC and platelet transfusion independence. - Duration of RBC transfusion independence, platelet transfusion independence, and platelet and RBC transfusion independence. - Time to first CR or PR (for HR MDS or CMML, or low-blast AML) and to first CR or CRi (for low-blast AML) when compared with single-agent azacitidine - Rates of HI in patients with HR MDS, patients with HR MDS/CMML, and patients with HR CMML - Patients who have inpatient hospital admission(s) related to HR MDS, CMML (collected through transformation to AML or until initiation of subsequent therapy, whichever occurs first) or low-blast AML (collected through initiation of subsequent therapy). - Time to PD, Relapse after CR (low-blast AML), Relapse after CR or PR (HR MDS/CMML), or Death. - HRQOL assessed using the - HRQOL assessed using the EORTC QLQ-C30. - Plasma concentration-time data for pevonedistat. - ORR, EFS and OS in patients that have TP53 mutations, 17p deletions | — |
Countries
Australia, Belgium, Brazil, Canada, Czechia, Czech Republic, France, Germany, Greece, Israel, Italy, Japan, Korea, Republic of, Mexico, Poland, Russian Federation, Spain, Sweden, Turkey, United Kingdom, United States
Contacts
Public ContactDrug Information Call Center
Millennium Pharmaceuticals, Inc.
Outcome results
None listed