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Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML)

NCT03268954

Description:

The purpose of this study is 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 AML in participants with MDS or CMML, whichever occurs first, and is defined as death in participants with low-blast AML).

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML)
  • Official Title: A Phase 3, Randomized, Controlled, Open-label, Clinical Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia

Clinical Trial IDs

  • ORG STUDY ID: Pevonedistat-3001
  • SECONDARY ID: 2017-000318-40
  • SECONDARY ID: U1111-1189-8055
  • SECONDARY ID: MOH_2018-02-04_002154
  • SECONDARY ID: JapicCTI-183848
  • NCT ID: NCT03268954

Conditions

  • Myelodysplastic Syndrome
  • Leukemia, Myelomonocytic, Chronic
  • Leukemia, Myeloid, Acute

Interventions

DrugSynonymsArms
AzacitidineAzacitidine + Pevonedistat
PevonedistatAzacitidine + Pevonedistat

Purpose

The purpose of this study is to determine whether the combination of pevonedistat and azacitidine improves overall response rate (ORR) by Cycle 6 and whether the combination of pevonedistat and azacitidine improves event-free survival (EFS) when compared with single-agent azacitidine.

Detailed Description

      The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to
      treat people with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic
      leukemia (CMML) and low-blast acute myelogenous leukemia (AML) as a combination treatment
      with azacitidine. This study will look at the overall survival, event-free survival and
      response to treatment in people who take pevonedistat and azacitidine when compared to people
      who take single-agent azacitidine.

      The study will enroll approximately 450 patients. Once enrolled, participants will be
      randomly assigned in 1:1 ratio (by chance, like flipping a coin) to one of the two treatment
      groups in 28-day treatment cycles:

        -  Pevonedistat 20 mg/m^2 and azacitidine 75 mg/m^2 combination

        -  Single-agent azacitidine 75 mg/m^2

      All participants will receive azacitidine via intravenous or subcutaneous route. Participants
      randomized to the combination arm will also receive pevonedistat intravenous infusion.

      This multi-center trial will be conducted worldwide. The overall time to participate in this
      study is approximately 63 months. Participants will attend the end-of-treatment visit 30 days
      after the last dose of study drug or before the start of subsequent anti-neoplastic therapy
      if that occurs sooner.

      Participants with HR MDS or CMML will have EFS follow-up study visits every month if their
      disease has not transformed to AML and they have not started subsequent therapy. Participants
      with low-blast AML will have response follow-up study visits every month until they relapse
      from CR or meet the criteria for PD. All participants will enter OS follow-up (contacted
      every 3 months) when they have confirmed transformation to AML (for participants with HR MDS
      or CMML at enrollment) or experienced PD or relapse from CR (for participants with low-blast
      AML at study enrollment).
    

Trial Arms

NameTypeDescriptionInterventions
Azacitidine + PevonedistatExperimentalAzacitidine 75 mg/m^2, intravenous or subcutaneous, on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m^2, 60-minute (±10) infusion, intravenous, on Days 1, 3, and 5 in 28-day treatment cycles up to 12 cycles.
  • Azacitidine
  • Pevonedistat
AzacitidineExperimentalAzacitidine 75 mg/m^2, intravenous or subcutaneous, on Days 1 to 5, Days 8 and 9 in 28-day treatment cycles up to 9 cycles.
  • Azacitidine

Eligibility 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] <13,000/μL) or low-blast acute myelogenous leukemia (AML).

          2. Has MDS or CMML and must also have one of the following Prognostic Risk Categories,
             based on the Revised International Prognostic Scoring System (IPSS-R):

               -  Very high (>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) 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 <61 years), +2 for (age 61-70 years), +4 for (age >71 years).

          -  + 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).

          -  + 0 for (platelets <50), +1 for (platelets >50).

        Exclusion Criteria:

          1. Has previous treatment for higher-risk myelodysplastic syndromes (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. 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., patients 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).

          4. Has either clinical evidence of or history of central nervous system involvement by
             AML.

          5. Has active uncontrolled infection or severe infectious disease, such as severe
             pneumonia, meningitis, or septicemia.

          6. 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.

          7. Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they
             have undergone resection.

          8. Has prothrombin time (PT) or aPTT >1.5× 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.

          9. Has known human immunodeficiency virus (HIV) seropositive.

         10. 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.

         11. Has known hepatic cirrhosis or severe preexisting hepatic impairment.

         12. 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.

         13. Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the
             first dose of pevonedistat.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with Overall Response by Cycle 6
Time Frame:Up to Cycle 6 (up to approximately Day 168)
Safety Issue:
Description:Responses for HR MDS/CMML are based on Modified International Working Group (IWG) Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. Overall response=complete remission (CR) and partial remission (PR) for HR MDS/CMML and CR+CR with incomplete blood count recovery (CRi)+PR for low-blast AML. CR for HR MDS/CMML:≤5% myeloblasts with normal maturation of all bone marrow cell lines,≥11g/dL hemoglobin (Hgb),≥100*10^9/L platelet (pl),≥1.0*10^9/L neutrophils, 0% blasts in peripheral blood, and PR:all CR criteria met except bone marrow blasts ≥50% decrease(dec) over pretreatment but still >5%. For low-blast AML-CR:morphologic leukemia-free state,>1.0*10^9 neutrophils, ≥100*10^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CRi: fulfill CR criteria except residual neutropenia <1.0*10^9/L/thrombocytopenia (pl<100*10^9/L); PR:all CR hematological values but ≥50% dec in percentage of blasts to 5%-25% in bone marrow aspirate.

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:From randomization until death : up to 6 years
Safety Issue:
Description:OS is calculated as the time from date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis will be censored as of the date the participant was last known to be alive.
Measure:Six-Month Survival Rate
Time Frame:Month 6
Safety Issue:
Description:Six-month survival rate is defined as Kaplan-Meier estimate of six-month survival rate.
Measure:One-Year Survival Rate
Time Frame:Month 12
Safety Issue:
Description:One-year survival rate is defined as Kaplan-Meier estimate of one-year survival rate.
Measure:Thirty-Day Survival Rate
Time Frame:Day 30
Safety Issue:
Description:Thirty-day survival rate is defined as Kaplan-Meier estimate of thirty-day survival rate.
Measure:Sixty-Day Survival Rate
Time Frame:Day 60
Safety Issue:
Description:Sixty-day survival rate is defined as Kaplan-Meier estimate of sixty-day survival rate.
Measure:Time to AML Transformation in HR MDS and CMML Participants
Time Frame:From randomization until transformation to AML : up to 6 years
Safety Issue:
Description:Time to AML transformation in HR MDS and CMML participants is defined as time from randomization to documented AML transformation. Participants who died before progression to AML will be censored. Transformation to AML is defined, according to WHO classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%.
Measure:Percentage of Participants with CR
Time Frame:From randomization until CR : up to 6 years
Safety Issue:
Description:Disease responses for HR MDS or CMML are based on the Modified IWG Response Criteria for MDS and for low-blast AML on the Revised IWG Response Criteria for AML. CR for HR MDS or CMML is defined as ≤5% myeloblasts with normal maturation of all cell lines in the bone marrow, and ≥11 g/dL Hgb, ≥100*10^9/L platelets (pl), ≥1.0*10^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of >1.0*10^9/L and pl of ≥1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia.
Measure:Percentage of Participants with CR and Marrow CR
Time Frame:From randomization until CR or marrow CR : up to 6 years
Safety Issue:
Description:Disease responses for HR MDS or CMML are based on the IWG Response Criteria for MDS and for low-blast AML on the Revised IWG Response Criteria for AML. CR for HR MDS or CMML is defined as ≤5% myeloblasts with normal maturation of all cell lines in the bone marrow, and ≥11 g/dL Hgb, ≥100*10^9/L platelets (pl), ≥1.0*10^9/L neutrophils and 0% blasts in peripheral blood. Marrow CR: Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment.
Measure:Percentage of Participants with CR, PR and Hematologic Improvement (HI)
Time Frame:From randomization until, CR, PR or HI : up to 6 years
Safety Issue:
Description:Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: ≤5% myeloblasts with normal maturation of all bone marrow cell lines,≥11 g/dL Hgb, ≥100*10^9/L pl, ≥1.0*10^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still >5%;HI: Hgb increase (inc) ≥1.5 g/dL if baseline<11 g/dL; pl inc ≥30*10^9/L if baseline >20*10^9/L or inc from <20*10^9/L to >20*10^9/L and by at least 100%; neutrophil inc by 100% and absolute inc of >0.5*10^9/L if baseline <1*10^9/L.
Measure:Percentage of Participants with CR and Marrow CR and PR
Time Frame:From randomization until CR or Marrow CR and PR : up to 6 years
Safety Issue:
Description:Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: ≤5% myeloblasts with normal maturation of all bone marrow cell lines, ≥11 g/dL Hgb, ≥100*10^9/L pl, ≥1.0*10^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment. PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still >5%.
Measure:Percentage of Participants with CR and Marrow CR, PR and Hematologic Improvement (HI)
Time Frame:From randomization until CR, marrow CR, PR or HI : up to 6 years
Safety Issue:
Description:Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: ≤5% myeloblasts with normal maturation of all bone marrow cell lines, ≥11 g/dL Hgb, ≥100*10^9/L pl, ≥1.0*10^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment. PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still>5%. HI: Hgb increase (inc) ≥1.5 g/dL if baseline <11 g/dL; pl inc ≥30*10^9/L if baseline>20*10^9/L or inc from <20*10^9/L to >20*10^9/L and by at least 100%; neutrophil inc by 100% and absolute inc of >0.5*10^9/L if baseline <1.0*10^9/L.
Measure:Percentage of Participants with Overall Response (OR)
Time Frame:From randomization until CR and PR or CR, CRi and PR : up to 6 years
Safety Issue:
Description:Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR and PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: ≤5% myeloblasts with normal maturation of all bone marrow cell lines, ≥11 g/dL Hgb, ≥100*10^9/L pl, ≥1.0*10^9/L neutrophils, 0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still>5%. For low-blast AML-CR:morphologic leukemia-free state>1.0*10^9 neutrophils, ≥100*10^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia <1.0*10^9/L or pl <100*10^9/L; PR: all CR hematological values but ≥50% decrease in bone marrow aspirate.
Measure:Percentage of Participants with Overall Response 2 (OR2)
Time Frame:From randomization until, CR, PR or HI : up to 6 years
Safety Issue:
Description:Overall response 2=CR, PR and HI for HR MDS/CMML and CR, CRi and PR for low-blast AML. For HR MDS/CMML-CR: ≤5% myeloblasts with normal maturation of all bone marrow cell lines, ≥11 g/dL Hgb, ≥100*10^9/L pl, ≥1.0*10^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still >5%;HI: Hgb increase (inc) ≥1.5 g/dL if baseline <11 g/dL; pl inc ≥30*10^9/L if baseline >20*10^9/L or inc from <20*10^9/L to >20*10^9/L and by 100%; and neutrophil inc by 100% and absolute inc of >0.5*10^9/L if baseline <100*10^9/L. For low-blast AML-CR: morphologic leukemia-free state >1.0*10^9 neutrophils, ≥100*10^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery: fulfill CR criteria except residual neutropenia <1.0*10^9/L or pl <100*10^9/L;PR: all CR hematological values but ≥50% decrease in bone marrow aspirate.
Measure:Duration of CR
Time Frame:From CR until first documentation of PD or transformation to AML : up to 6 years
Safety Issue:
Description:Duration of CR is defined as the first documented CR to the first documentation of progressive disease (PD) or transformation to AML. Disease responses for HR MDS or CMML are based on the Modified International Working Group (IWG) Response Criteria for MDS and for low-blast AML on the Revised IWG Response Criteria for AML. CR for HR MDS or CMML is defined as ≤5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to ≥11 g/dL hemoglobin (Hgb), ≥100*10^9/liter (/L) platelets (pl), ≥1.0*10^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0*10^9/L and pl of ≥100*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (pl <100*10^9/L).
Measure:Duration of Overall Response (OR)
Time Frame:From CR and PR or CR, CRi and PR to the first documented PD or transformation to AML : up to 6 years
Safety Issue:
Description:Duration of OR is defined as documented response to the first documentation of PD or transformation to AML. Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR and PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: ≤5% myeloblasts with normal maturation of all bone marrow cell lines, ≥11 g/dL Hgb, ≥100*10^9/L pl, ≥1.0*10^9/L neutrophils, 0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still >5%. For low-blast AML-CR: morphologic leukemia-free state >1.0*10^9 neutrophils, ≥100*10^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia <1.0*10^9/L or pl <100*10^9/L; PR: all CR hematological values but ≥50% decrease in % of blasts in bone marrow aspirate.
Measure:Duration of Overall Response 2 (OR2)
Time Frame:From documented CR, PR or HI to the first documented PD or transformation to AML : up to 6 years
Safety Issue:
Description:Duration of OR2 is defined as documented response to first documented PD or transformation to AML. OR2=CR,PR,HI for MDS/CMML and CR,CRi,PR for low-blast AML. For HR MDS/CMML-CR: ≤5% myeloblasts with normal maturation of all bone marrow cell lines, ≥11 g/dL Hgb, ≥100*10^9/L pl, ≥1.0*10^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still >5%; HI: Hgb inc ≥1.5 g/dL if baseline <11 g/dL; pl inc ≥30*10^9/L if baseline >20*10^9/L or inc from <20*10^9/L to >20*10^9/L by at least 100%; neutrophil inc by 100% and absolute inc of >0.5*10^9/L if baseline <1.0*10^9/L. For low-blast AML-CR: morphologic leukemia-free state, >1.0*10^9 neutrophils, ≥100*10^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CRi: fulfill CR criteria except residual neutropenia <1.0*10^9/L or pl <100*10^9/L; PR: all CR hematological values but ≥50% decrease in bone marrow aspirate.
Measure:Percentage of Participants with Red Blood Cells (RBCs) and Platelet-transfusion Independence
Time Frame:8 weeks before randomization through 30 days after last dose of any study drug : up to 6 years
Safety Issue:
Description:A participant is defined as RBC or platelet-transfusion independent if he/she receives no RBC or platelet transfusions for a period of at least 8 weeks before randomization through 30 days after the last dose of any study drug. Rate of transfusion independence is defined as number of participants who become transfusion independent divided by the number of participants who are transfusion dependent at Baseline.
Measure:Duration of Red Blood Cells (RBCs) and Platelet-transfusion Independence
Time Frame:First established transfusion independence to subsequent RBC or Platelet transfusion : up to 6 years
Safety Issue:
Description:Duration of RBC and Platelet transfusion independence is defined as the time from the first established RBC and/or platelet transfusion independence to the subsequent first RBC and/or platelet transfusion.
Measure:Time to First CR or PR
Time Frame:From randomization until CR or PR : up to 6 years
Safety Issue:
Description:Time to first CR or PR is defined as the time from randomization to first documented CR or PR, whichever occurs first. Disease responses for HR MDS or CMML are based on Modified IWG Response Criteria for MDS and for low-blast AML on Revised IWG Response Criteria for AML. For HR MDS or CMML-CR: ≤5% myeloblasts with normal maturation of all bone marrow cell lines, ≥11 g/dL Hgb, ≥100*10^9/L pl, ≥1.0*10^9/L neutrophils, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still >5%; For low-blast AML-CR: morphologic leukemia-free state, >1.0*10^9/L neutrophils, pl ≥100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery: fulfill CR criteria except residual neutropenia <1.0*10^9/L or pl <100*10^9/L; PR: all CR hematological values but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate.
Measure:Percentage of Participants with Hematologic Improvement (HI)
Time Frame:From randomization until HI : up to 6 years
Safety Issue:
Description:Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. HI: Hgb increase (inc)≥1.5 g/dL if baseline <11 g/dL; pl inc ≥30*10^9/L if baseline >20*10^9/L or inc from <20*10^9/L to >20*10^9/L by at least 100%; neutrophil inc by 100% and absolute inc of >0.5*10^9/L if baseline <1.0*10^9/L.
Measure:Percentage of Participants with at least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML
Time Frame:From randomization until transformation to AML or until initiation of subsequent therapy up to approximately up to 6 years
Safety Issue:
Description:Inpatient hospital admission data will be collected through transformation to AML (HR MDS/CMML participants) or disease progression (low-blast AML participants) or until initiation of subsequent therapy (all participants), whichever occurs first. Transformation to AML is defined, according to WHO Classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%.
Measure:Time to Progressive Disease (PD), Relapse or Death
Time Frame:From randomization until PD, relapse after CR or death : up to 6 years
Safety Issue:
Description:In HR MDS/CMML, PD: 1) for participants with <5% blasts: ≥50% inc to >5% blasts, with 5%-10% blasts: ≥50% inc to >10% blasts, with 10%-20% blasts: ≥50% inc to >20% blasts, with 20%-30% blasts: >50% inc in bone marrow blasts to >30% blasts, >50% inc in circulating blasts to >30% blasts in peripheral blood/development of biopsy-proven extramedullary disease/new sites of extramedullary leukemia; 2) at least 50% decrement from maximum remission/response in granulocytes or pl or reduction in Hgb by ≥2 g/dL or new transfusion dependence. Relapse after CR or PR: either return to pretreatment bone marrow blast percentage/Decrement of ≥50% from maximum remission/response levels in granulocytes or pl/Reduction in Hgb concentration by ≥1.5 g/dL/transfusion dependence. In AML, PD: 1) >50% inc in bone marrow blasts to >30% blasts, 2) >50% inc in circulating blasts to >30% blasts in peripheral blood 3) Development of biopsy-proven extramedullary disease/new sites of extramedullary leukemia.
Measure:Health-Related Quality of Life (HRQOL) using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30
Time Frame:Baseline Up to 6 years
Safety Issue:
Description:The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. Most of the 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QOL scale, higher scores represent better QOL; for the symptom scales, lower scores represent better QOL.
Measure:Plasma Concentration of Pevonedistat
Time Frame:Cycle 1 Day 1 predose and multiple time points (up to 4 hours) post dose; Cycle 1 Days 3 and 5 predose; Cycle 2 and 4 Day 1 at multiple time points (up to 3 hours) post dose; Cycle 4 Day 3 predose
Safety Issue:
Description:
Measure:Percentage of Participants with Overall Response in Participants who have TP53 Mutations, 17p Deletions, and/or are Determined to be in an Adverse Cytogenetic Risk Group
Time Frame:From randomization until CR, CRi and PR : up to 6 years
Safety Issue:
Description:Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS; for low-blast AML on Revised IWG Response Criteria for AML. Overall response=CR and PR for HR MDS/CMML and CR + CRi + PR for low-blast AML. CR for HR MDS/CMML: ≤5% myeloblasts with normal maturation of all bone marrow cell lines, ≥11 g/dL Hgb, ≥100*10^9/L pl, ≥1.0*10^9/L neutrophils,0% blasts in peripheral blood and PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still>5%. For low-blast AML-CR: morphologic leukemia-free state, >1.0*10^9 neutrophils, ≥100*10^9/L pl, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery (CRi): fulfill CR criteria except residual neutropenia <1.0*10^9/L or pl <100*10^9/L; PR: all CR hematological values but ≥50% decrease in the percentage of blasts to 5% to 25% in bone marrow aspirate.
Measure:Event-Free Survival in Participants who have TP53 Mutations, 17p Deletions, and/or are Determined to be in an Adverse Cytogenetic Risk Group
Time Frame:From randomization until transformation to AML if eligible or death : up to 6 years
Safety Issue:
Description:Event is defined as death or transformation to AML in participants with MDS or CMML, which ever occurs first. Transformation to AML is defined, according to world health organization (WHO) Classification as a participant having >20% blasts in the blood or marrow and increase of blast count by 50%. Event is defined as death in participants with low-blast AML.
Measure:Overall Survival in Participants who have TP53 Mutations, 17p Deletions, and/or are Determined to be in an Adverse Cytogenetic Risk Group
Time Frame:From randomization until death : up to 6 years
Safety Issue:
Description:OS is calculated from date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis will be censored as of the date the participant was last known to be alive.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • Drug therapy

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