Acute myeloid leukemia (AML) and Myelodysplastic syndromes (MDS) with impending hematological relapse MedDRA version: 21.1 Level: PT Classification code 10000880 Term: Acute myeloid leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10028533 Term: Myelodysplastic syndrome System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Pevonedistat
Product Code: MLN4929
Pharmaceutical Form: Concentrate and solvent for solution for infusion
INN or Proposed INN: PEVONEDISTAT
CAS Number: 905579-51-3
Current Sponsor code:
Sponsors
Leipzig University
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - AML or MDS - continuing first CR after conventional intensive chemotherapy OR continuing CR after alloSCT - MRD positivity (assessed by local lab) as defined by: o NPM1mut status >1% in peripheral blood or bone marrow in NPM1 mutated patients at diagnosis or o Patients after allogeneic transplantation, who were NPM1 unmutated at diagnosis and have a blood or marrow CD34/CD117 chimerism =65 years) yes F.1.3.1 Number of subjects for this age range 26
Exclusion criteria
Exclusion criteria: Compliance with major study procedures - Patient does not accept bone marrow sampling during screening, primary end point visit and after the treatment. - Patient does not accept several blood sampling during screening, treatment (up to bi-daily) and after the treatment. Safety - Inadequate organ function as defined in the list below: o Absolute neutrophil count (ANC) 1.5xupper limit of normal (ULN)19 except in patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome may be enrolled if direct bilirubin > 1.5x ULN of the direct bilirubin. o Both Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3.0 ULN - ECOG performance status of =2 Concomitant Diseases - Liver cirrhosis or severe pre-existing hepatic impairment - Known severe cardiopulmonary disease (e.g. unstable angina, congestive heart failure NYHA III or IV, myocardial infarction within 6 months prior to screening, symptomatic cardiomyopathy, clinically significant arrhythmia20, clinically significant pulmonary hypertension requiring pharmacologic therapy) - Uncontrolled high blood pressure (i.e. systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg) - Known prolonged rate corrected QT interval = 500 msec, calculated according to institutional guidelines - Known left ventricular ejection fraction < 50% as assessed by echocardiogram or radionuclide angiography - Known moderate to severe symptomatic chronic obstructive pulmonary disease, interstitial lung disease, or pulmonary fibrosis - Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia - Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. - Known Human Immunodeficiency Virus (HIV 1/2 antibodies) - Known active Hepatitis B (i.e. HBsAg reactive) or Hepatitis C (i.e., HCV RNA [qualitative] is detected). NOTE: Patients 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. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load. - Major surgery within 14 days of randomization or a scheduled surgery during study period - Known central nervous system (CNS) involvement - Diagnosis or treatment for another malignancy within 2 years before randomization. (NOTE: Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection. Prior diagnosis of myelodysplasia, myeloproliferative neoplasm, or aplastic anemia and treatment for that diagnosis does not lead to exclusion) - Any evidence of residual disease of another malignancy - Patients with uncontrolled coagulopathy or bleeding disorder - History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the in the best interest of the subject to participate, in the opinion of the treating investigator Prior unfavourable effect of HMA monotherapy - Prior HMA failure - Prior HMA treatment without subsequent allogeneic transplantation Interfering Treatments - An
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To show that pevonedistat and azacitidine are more effective compared to azacitidine alone with regard to achievement of MRD negativity after 3 months of treatment;Secondary Objective: To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option: Time to event endpoints: - Overall Survival (OS): Time from randomization until death from any cause - Relapse Free Survival (RFS): Time from randomization until hematological relapse or death from any cause (whichever comes first) Time to event endpoints with competing risks: - Cumulative incidence of documented MRD negativity with death, hematological relapse and transplant as competing events - Cumulative incidence of hematological relapse with death and transplant as competing events - Quality of life - Rate and severity of adverse events for patients treated with pevonedistat and azacitidine;Primary end point(s): - Rate of documented MRD negativity after three cycles of treatment ;Timepoint(s) of evaluation of this end point: Patients who do not receive three cycles for any reason (e.g. hematological relapse, toxicity), patients without valid MRD assessment after three cycles, as well as patients in whom the | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Overall Survival (OS) - Relapse Free Survival (RFS) - Cumulative incidence of documented MRD negativity with death, hematological relapse and transplant as competing events - Cumulative incidence of hematological relapse with death and transplant as competing events - Rate of conversion to MRD negativity among patients crossing over from the control to the experimental arm after three crossed-over cycles - Rate and CTC graded severity of adverse events for patients treated with PEV and AZA combination therapy and with AZA alone - Impact on quality of life;Timepoint(s) of evaluation of this end point: OS = Time from randomization until death from any cause. RFS = Time from randomization until hematological relapse or death from any cause (whichever comes first). | — |
Countries
Germany
Contacts
Public ContactSusanne Melzer
Zentrum für Klinische Studien Leipzig
Outcome results
None listed