Acute Myeloid Leukemia in Remission, Minimal Residual Disease, Myelodysplastic Syndromes
Conditions
Brief summary
MDS/AML with MRD and impending relapse after allogeneic stem cell transplantation and/or conventional chemotherapy
Detailed description
Experimental arm: pevonedistat in combination with azacitidine Control arm: azacitidine alone With the following modifications: * Patients on the azacitidine arm and still MRD+ at 3 months but without hematological relapse can cross over to the combination arm * Cross over into the combination arm is possible any time up to 9 months of study treatment if initially responding patients (at 3 months) on AZA monotherapy become MRD positive again * Maximum treatment duration of 1 year * Patients receive pevonedistat at 20 mg/m2 i.v. (d1,3,5, q4w); azacitidine is given at a standard dose of 75 mg/m² i.v. or s.c. (d1-7 or 1-5,8,9, q4w)
Interventions
DRUGPevonedistat
Patients receive pevonedistat at 20 mg/m2 i.v. (d1,3,5, q4w) up to 12 cycles
DRUGAzacitidine
azacitidine is given at a standard dose of 75 mg/m² (d1-7 or 1-5,8,9, q4w) up to 12 cycles
Sponsors
Millennium Pharmaceuticals, Inc.
University of Leipzig
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
With Cross-Over option
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* AML or MDS * continuing first CR after conventional intensive chemotherapy OR continuing CR after alloSCT * Confirmed MRD positivity (assessed by central lab) as defined by: * NPM1mut status \>1% in peripheral blood or bone marrow in NPM1 mutated patients at diagnosis or * Patients after allogeneic transplantation, who were NPM1 unmutated at diagnosis and have a blood or marrow CD34/CD117 chimerism \<80%
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: * White blood cell (WBC) count \> 50 Gpt/L before administration of pevonedistat on Cycle 1 Day 1 * Absolute neutrophil count (ANC) \< 1.5 Gpt/L * Platelets \< 100 Gpt/L * Albumin \< 2.7 g/dL * Creatinine clearance \< 30 mL/min (Cockcroft und Gault formula) * Total bilirubin \> 1.5xupper limit of normal (ULN) 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. * Both Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \> 3.0 ULN * ECOG performance status of ≥2 Concomitant Diseases * Hematological relapse * 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 arrhythmia, 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) * Confirmed prolonged rate corrected QT interval ≥ 500 msec, calculated according to institutional guidelines (Screening ECG) * Confirmed left ventricular ejection fraction \< 50% as assessed by echocardiogram or radionuclide angiography (Screening TTE) * 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 best interest of the subject to participate, in the opinion of the treating investigator Unexpected effect of HMA monotherapy * Prior HMA failure * Prior HMA treatment without subsequent allogeneic transplantation Interfering Treatments * Any ongoing therapy with investigational agents or chemotherapeutic agents active against MDS or AML * BCRP inhibitors (for exceptions, see section 5.7.5) are not permitted during the study and should be stopped 14 days before first dose of the study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Measurable residual disease (MRD) status after 3 months of treatment | 3 months after start of treatment | 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. MRD assessment is carried out as determination of the NPM1mut status or as CD34/CD117 chimerism analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From date of randomization until the date of death from any cause, assessed up to 25 months | To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option. |
| Relapse Free Survival | Time from randomization until hematological relapse or death from any cause (whichever comes first), assessed up to 25 Months. | To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option. |
| Impact of treatment assessed by using the validated questionnaires EORTC QLQ-C30. | Time from randomization until hematological relapse or death from any cause (whichever comes first) | To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option. |
| Impact of treatment assessed by using the validated questionnaires EQ-5D-5L. | Time from randomization until hematological relapse or death from any cause (whichever comes first), assessed up to 25 months. | To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option. |
Countries
Germany
Outcome results
None listed