Treatment of MDS/AML Patients With an Impending Hematological Relapse With AZA or ATA and Pevonedistat
Primary Purpose
Acute Myeloid Leukemia in Remission, Myelodysplastic Syndromes, Minimal Residual Disease
Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Pevonedistat
Azacitidine
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia in Remission
Eligibility Criteria
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
Exclusion criteria regarding special restrictions for females of childbearing potential
- Current or planned pregnancy or nursing women (negative urine or serum pregnancy test within 3 days prior to receiving study treatment is needed. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test needs to be required.)
- Female patients of childbearing potential, who are not using or not willing to use 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).
Exclusion criteria regarding special restrictions for males, even if surgically sterilized (i.e. status post vasectomy)
- Male patients, who do not agree to use an adequate method of contraception, starting with the first dose of study therapy during the entire study treatment period and through 4 months after the last dose of study drug. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).
Regulatory requirements
- Age under 18 years at registration
- Inability to provide written informed consent
- Subject without legal capacity who is unable to understand the nature, scope, significance and consequences of this clinical trial
- Simultaneous participation in another interventional clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to SHAPE trial beginning
Sites / Locations
- Medizinische Klinik IV - Hämatologie und Onkologie, Universitätsklinikum Aachen
- Zentrum Hämatologie, Onkologie, Palliativmedizin, Helios Klinikum Berlin-Buch GmbH
- Klinik für Innere Medizin III, Hämatologie, Onkologie, Stammzelltransplantation, Klinikum Chemnitz gGmbH
- Hämatologie/Internistische Onkologie, Onkologische Tagesklinik
- Medizinischen Klinik und Poliklinik I / Hämatologie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
- Klinik für Hämatologie, Universitätsklinikum Essen
- Universitätsklinik und Poliklinik für Innere Medizin IV, Onkologie, Hämatologie, Universitätsklinikum Halle (Saale)
- Klinik und Poliklinik für Innere Medizin II/Hämat. - Onkologie, Universitätsklinikum Jena
- Klinik für Innere Medizin II/ Hämatologie und Onkologie, Univ.Klinikum Schleswig-Holstein/Campus Kiel
- Medizinische Klinik und Poliklinik I - Hämatologie und Zelltherapie, Hämostaseologie, Leipzig University
- Innere Medizin A/Hämatologie-Onkologie, Universitätsklinik Münster
- Klinik für Hämatologie, Onkologie & Stammzelltherapie, Helios-Klinikum Schwerin
- Klinik Innere Medizin III - Onko-, Häma- u. Palliativmedizin, Diakonie-Klinikum Schwäbisch Hall gGmbH
- Abteilung für Hämatologie, Onkologie und Palliativmedizin, Robert-Bosch-Krankenhaus Stuttgart
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Other
Arm Label
pevonedistat + azacitidine
azacitidine monotherapy
Arm Description
pevonedistat in combination with azacitidine
administration of azacitidine monotherapy
Outcomes
Primary Outcome Measures
Measurable residual disease (MRD) status after 3 months 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 Outcome Measures
Overall Survival
To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option.
Relapse Free Survival
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.
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.
To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option.
Full Information
NCT ID
NCT04712942
First Posted
December 18, 2020
Last Updated
August 17, 2023
Sponsor
University of Leipzig
Collaborators
Millennium Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT04712942
Brief Title
Treatment of MDS/AML Patients With an Impending Hematological Relapse With AZA or ATA and Pevonedistat
Official Title
Treatment of MDS/AML Patients With an Impending Hematological Relapse With Azacitidine Alone or in Combination With PEvonedistat - a Randomized Phase 2 Trial
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
January 1, 2021 (Actual)
Primary Completion Date
January 31, 2023 (Actual)
Study Completion Date
January 31, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Leipzig
Collaborators
Millennium Pharmaceuticals, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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)
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia in Remission, Myelodysplastic Syndromes, Minimal Residual Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
With Cross-Over option
Masking
None (Open Label)
Allocation
Randomized
Enrollment
14 (Actual)
8. Arms, Groups, and Interventions
Arm Title
pevonedistat + azacitidine
Arm Type
Experimental
Arm Description
pevonedistat in combination with azacitidine
Arm Title
azacitidine monotherapy
Arm Type
Other
Arm Description
administration of azacitidine monotherapy
Intervention Type
Drug
Intervention Name(s)
Pevonedistat
Intervention Description
Patients receive pevonedistat at 20 mg/m2 i.v. (d1,3,5, q4w) up to 12 cycles
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
azacitidine is given at a standard dose of 75 mg/m² (d1-7 or 1-5,8,9, q4w) up to 12 cycles
Primary Outcome Measure Information:
Title
Measurable residual disease (MRD) status after 3 months of treatment
Description
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.
Time Frame
3 months after start of treatment
Secondary Outcome Measure Information:
Title
Overall Survival
Description
To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option.
Time Frame
From date of randomization until the date of death from any cause, assessed up to 25 months
Title
Relapse Free Survival
Description
To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option.
Time Frame
Time from randomization until hematological relapse or death from any cause (whichever comes first), assessed up to 25 Months.
Title
Impact of treatment assessed by using the validated questionnaires EORTC QLQ-C30.
Description
To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option.
Time Frame
Time from randomization until hematological relapse or death from any cause (whichever comes first)
Title
Impact of treatment assessed by using the validated questionnaires EQ-5D-5L.
Description
To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option.
Time Frame
Time from randomization until hematological relapse or death from any cause (whichever comes first), assessed up to 25 months.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Exclusion criteria regarding special restrictions for females of childbearing potential
Current or planned pregnancy or nursing women (negative urine or serum pregnancy test within 3 days prior to receiving study treatment is needed. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test needs to be required.)
Female patients of childbearing potential, who are not using or not willing to use 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).
Exclusion criteria regarding special restrictions for males, even if surgically sterilized (i.e. status post vasectomy)
Male patients, who do not agree to use an adequate method of contraception, starting with the first dose of study therapy during the entire study treatment period and through 4 months after the last dose of study drug. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).
Regulatory requirements
Age under 18 years at registration
Inability to provide written informed consent
Subject without legal capacity who is unable to understand the nature, scope, significance and consequences of this clinical trial
Simultaneous participation in another interventional clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to SHAPE trial beginning
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Uwe Platzbecker, Prof. Dr.
Organizational Affiliation
University Leipzig
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medizinische Klinik IV - Hämatologie und Onkologie, Universitätsklinikum Aachen
City
Aachen
ZIP/Postal Code
52074
Country
Germany
Facility Name
Zentrum Hämatologie, Onkologie, Palliativmedizin, Helios Klinikum Berlin-Buch GmbH
City
Berlin
ZIP/Postal Code
13125
Country
Germany
Facility Name
Klinik für Innere Medizin III, Hämatologie, Onkologie, Stammzelltransplantation, Klinikum Chemnitz gGmbH
City
Chemnitz
ZIP/Postal Code
09113
Country
Germany
Facility Name
Hämatologie/Internistische Onkologie, Onkologische Tagesklinik
City
Cottbus
ZIP/Postal Code
03048
Country
Germany
Facility Name
Medizinischen Klinik und Poliklinik I / Hämatologie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
City
Dresden
ZIP/Postal Code
01304
Country
Germany
Facility Name
Klinik für Hämatologie, Universitätsklinikum Essen
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Universitätsklinik und Poliklinik für Innere Medizin IV, Onkologie, Hämatologie, Universitätsklinikum Halle (Saale)
City
Halle (Saale)
ZIP/Postal Code
06120
Country
Germany
Facility Name
Klinik und Poliklinik für Innere Medizin II/Hämat. - Onkologie, Universitätsklinikum Jena
City
Jena
ZIP/Postal Code
07740
Country
Germany
Facility Name
Klinik für Innere Medizin II/ Hämatologie und Onkologie, Univ.Klinikum Schleswig-Holstein/Campus Kiel
City
Kiel
ZIP/Postal Code
24105
Country
Germany
Facility Name
Medizinische Klinik und Poliklinik I - Hämatologie und Zelltherapie, Hämostaseologie, Leipzig University
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Innere Medizin A/Hämatologie-Onkologie, Universitätsklinik Münster
City
Münster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Klinik für Hämatologie, Onkologie & Stammzelltherapie, Helios-Klinikum Schwerin
City
Schwerin
ZIP/Postal Code
19049
Country
Germany
Facility Name
Klinik Innere Medizin III - Onko-, Häma- u. Palliativmedizin, Diakonie-Klinikum Schwäbisch Hall gGmbH
City
Schwäbisch Hall
ZIP/Postal Code
74523
Country
Germany
Facility Name
Abteilung für Hämatologie, Onkologie und Palliativmedizin, Robert-Bosch-Krankenhaus Stuttgart
City
Stuttgart
ZIP/Postal Code
70376
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Treatment of MDS/AML Patients With an Impending Hematological Relapse With AZA or ATA and Pevonedistat
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