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An Efficacy and Safety Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML) and Low-Blast Acute Myelogenous Leukemia (AML)

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ClinicalTrials.gov Identifier: NCT02610777
Recruitment Status : Active, not recruiting
First Posted : November 20, 2015
Last Update Posted : November 19, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
The purpose of this study is to evaluate the efficacy and safety of pevonedistat plus azacitidine versus single-agent azacitidine in participants with HR-MDS or CMML, or low-blast AML.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Leukemia, Myelomonocytic, Chronic Leukemia, Myeloid, Acute Drug: Azacitidine Drug: Pevonedistat Phase 2

Detailed Description:

The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to treat people with MDS or CMML, or low-blast 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 120 participants. Once enrolled, participants will be randomly assigned (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 44 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 will enter event-free survival follow-up or response follow-up (study visits every 3 months) if their disease has not transformed to AML (for participants with HR MDS or CMML) or progressed (for participants with low-blast AML), and they have not started subsequent therapy. Participants will also enter overall survival follow-up (contacted every 3 months to document subsequent therapies and survival status).


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Low-Blast Acute Myelogenous Leukemia
Actual Study Start Date : April 14, 2016
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : March 31, 2020


Arm Intervention/treatment
Active Comparator: Azacitidine
Azacitidine 75 milligram per square meter (mg/m^2), intravenously or subcutaneously, on Days 1 to 5, Days 8 and 9 in 28-day treatment cycles.
Drug: Azacitidine
Azacitidine intravenous or subcutaneous formulation.

Experimental: Azacitidine + Pevonedistat
Azacitidine 75 mg/m^2, intravenously or subcutaneously, on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m^2, 60-minute (±10) infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles.
Drug: Azacitidine
Azacitidine intravenous or subcutaneous formulation.

Drug: Pevonedistat
Pevonedistat intravenous infusion.




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: From randomization until death up to 44 months ]
    OS will be 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, or the data cut-off date, whichever is earlier.


Secondary Outcome Measures :
  1. Event-Free Survival (EFS) [ Time Frame: From randomization until transformation to AML, or death due to any cause, up to 44 months ]
    EFS is defined as time from randomization until transformation to AML or death due to any cause whichever occurs first for participants with HR MDS or CMML, or death due to any cause for participants with low-blast AML. Transformation to AML is defined as a participant having greater than (>) 20 percent (%) blasts in blood or marrow and increase of blast count by 50%.

  2. Six-month Survival Rate [ Time Frame: Month 6 ]
    Six-month survival rate is defined as the Kaplan-Meier estimate of survival rate at 6-month.

  3. One-year Survival Rate [ Time Frame: Month 12 ]
    One -year survival rate is defined as the Kaplan-Meier estimate of survival rate at 1-year.

  4. Time to AML Transformation in HR MDS or CMML Participants [ Time Frame: From randomization until transformation to AML, up to 44 months ]
    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 World Health Organization (WHO) classification, as a participant having >20% blasts in the blood or marrow and increase of blast count by 50%.

  5. Percentage of Participants With Complete Remission (CR) [ Time Frame: From randomization until CR, up to 44 months ]
    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 less than or equal to (<=) 5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to (>=) 11 gram/deciliter (g/dL) hemoglobin (Hb), >=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 >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP) (<100*10^9/L).

  6. Percentage of Participants With CR and Partial Remission (PR) [ Time Frame: From randomization until CR and PR, up to 44 months ]
    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. CR for HR MDS or CMML:<=5% myeloblasts with normal maturation of all cell lines in bone marrow, and>=11 g/dL Hb; >=100*10^9/L pl;>=1.0*10^9/L neutrophils and 0% blasts in peripheral blood. PR for HR MDS or CMML: considered achieved if all CR criteria is met except for bone marrow blasts decreased by>=50% over pretreatment but still>5%.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, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<100*10^9/L)/TTP(<100*10^9/L). PR for low-blast AML: all hematological values for CR but with a decrease of at least 50% in percentage of blasts to 5% to 25% in bone marrow aspirate.

  7. Percentage of Participants With Overall Response [ Time Frame: From randomization until, CR, PR, or hematologic improvement (HI), up to 44 months ]
    Disease responses(HR MDS/CMML)based on modified IWG criteria for MDS;low-blast(LB)AML on revised IWG criteria for AML.Overall response in HR MDS/CMML=CR,PR/HI,in LB AML=CR+complete remission with incomplete blood count recovery(Cri)+PR.For HR MDS/CMML-CR:<=5% myeloblasts with normal maturation of all bone marrow cell lines,>=11g/dL Hb,>=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:hb increase(inc)>=1.5g/dL if baseline<11g/dL;pl inc>=30*10^9/L if baseline>20*10^9/L/inc from<20*10^9/L to >20*10^9/L,neutrophil inc by100%and absolute inc of>0.5*10^9/L if baseline<100*10^9/L.For LB AML-CR:morphologic leukemia-freestate>1.0*10^9neutrophils,>=100*10^9/Lpl,transfusion independence,no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR hematological values but>=50%decrease in bone marrow aspirate.

  8. Percentage of Participants with CR in low-blast AML [ Time Frame: From randomization until CR, up to 44 months ]
    Disease response for low-blast AML is based on the revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0*10^9/L and pl of >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP) (<100*10^9/L).

  9. Percentage of Participants With CR by Cycle 4 [ Time Frame: From randomization until CR by Cycle 4 (cycle length is equal to [=] 28 days) ]
    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. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=100*10^9/L pl, neutrophils >=1.0*10^9/L 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, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L).

  10. Percentage of Participants With CR and PR by Cycle 4 [ Time Frame: From randomization until CR and PR, by Cycle 4 (cycle length=28 days) ]
    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,PR or HI. For HR MDS/CMML-CR:<=5% myeloblasts with normal maturation of all bone marrow cell lines,>=11 g/dL Hb,>=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:>=1.5 g/dL hb inc if baseline<11 g/dL;>=30*10^9/L pl inc if baseline>20*10^9/L or inc from<20*10^9/L to >20*10^9/L, and neutrophils inc by 100% and > baseline<100*10^9/L. 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, pl <100*10^9/L; PR: all CR hematological values but >=50% decrease in bone marrow aspirate.

  11. Percentage of Participants With Overall Response by Cycle 4 [ Time Frame: From randomization until CR, PR or HI, by Cycle 4 (cycle length=28 days) ]
    Disease responses for HR MDS/CMML based on modified IWG response criteria for MDS;for LB AML on revised IWG response criteria for AML. Overall response=CR,PR or HI. For HR MDS/CMML-CR:<=5% myeloblasts with normal maturation of all bone marrow cell lines,>=11 g/dL Hb,>=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:>=1.5 g/dL hb inc if baseline<11 g/dL;pl inc>=30*10^9/L inc if baseline>20*10^9/L or inc from<20*10^9/L to >20*10^9/L and neutrophils inc by 100% and absolute inc of >0.5*10^9 if baseline<100*10^9/L. 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/TTP <100*10^9/L;PR:all CR hematological values but>=50% decrease in bone marrow aspirate.

  12. Percentage of Participants with CR in low-blast AML by Cycle 4 [ Time Frame: From randomization until CR by Cycle 4 (cycle length=28 days) ]
    Disease response for low-blast AML is based on revised IWG response criteria for AML. 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, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L).

  13. Duration of CR [ Time Frame: From randomization until CR, up to 44 months ]
    Duration of CR will be analyzed using standard survival analysis techniques based on Kaplan Meier estimates. 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. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=100*10^9/L 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, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L).

  14. Duration of CR and PR [ Time Frame: From randomization until CR or PR, up to 44 months ]
    Duration of CR and PR will be analyzed using standard survival analysis techniques based on Kaplan Meier estimates. 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 Hb, >=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/TTP <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.

  15. Duration of Overall Response [ Time Frame: From randomization until, CR, PR or HI, up to 44 months ]
    Disease responses for HR MDS/CMML based on modified IWG response criteria for MDS;for LB AML on revised IWG response criteria for AML. Overall response=CR,PR or HI. For HR MDS/CMML-CR:<=5% myeloblasts with normal maturation of all bone marrow cell lines,>=11 g/dL Hb,>=100*10^9/L pl, neutrophils>=1.0*10^9/L,0% blasts in peripheral blood; PR:all CR criteria met except bone marrow blasts>=50% decrease over pretreatment but still >5%;HI:>=1.5 g/dL hb inc 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 neutrophil inc by 100% and absolute inc of >0.5*10^9 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/TTP<100*10^9/L; PR: all CR hematological values but >=50% decrease in bone marrow aspirate.

  16. Duration of CR in low-blast AML [ Time Frame: From randomization until CR, up to 44 months ]
    Duration of CR will be analyzed using standard survival analysis techniques based on Kaplan Meier estimates. Disease responses for low-blast AML is based on revised IWG response criteria for AML. 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, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L).

  17. Time to First CR or PR [ Time Frame: From randomization until CR or PR, up to 44 months ]
    Time to first CR or PR: 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 Hb, >=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/TTP <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.

  18. Time to Subsequent Therapy [ Time Frame: From randomization up to 44 months ]
    Time to subsequent therapy is defined as time from randomization to the date of the first subsequent therapy. Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity. Participants who discontinue study treatment to receive single-agent azacitidine off study will not be counted as receiving subsequent therapy.

  19. 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 44 months) ]
    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.

  20. 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 44 months ]
    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%.

  21. Time to Progressive Disease (PD), Relapse, or Death [ Time Frame: From randomization until PD, relapse or death, up to 44 months ]
    Time from randomization until PD/transformation to AML/ relapse/death due to any cause,whichever occurs first.Relapse after CR or PR in MDS/CMML:return to pretreatment bone marrow blast percentage or decrement of >=50% from maximum remission levels in neutrophils or pl, reduction in Hb concentration by >=1.5 g/dL or transfusion dependence.PD:at least 50% decrement from maximum remission in neutrophils or pl, or reduction in Hb by >=2 g/dL or transfusion dependence;participants with <5% blasts:>=50% increase in blasts to >5% blasts; 5%-10% blasts:>=50% increase to >10% blasts;10%-20% blasts:>=50% increase to >20% blasts; 20%-30% blasts:>=50% increase to >30% blasts.Relapse after CR in Low blast AML: reappearance of leukemic blasts in peripheral blood or >=5% blasts in bone marrow not attributable to any cause (example, bone marrow regeneration after consolidation therapy).If there are no circulating blasts,bone marrow contains 5%-20% blasts, a repeat analysis is performed a week later.

  22. Number of Participants Reporting one or More Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Randomization up to 30 days after administration of the last dose of any study drug (up to 44 months) ]
    An AE is any untoward medical occurrence in a participant who will receive study drug without regard to possibility of causal relationship. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; or a medically important event. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

  23. Number of Participants With Markedly Abnormal Clinical Laboratory Values [ Time Frame: Randomization up to 44 months ]
    The number of participants with any markedly abnormal standard safety laboratory values will be collected throughout study.

  24. Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: Randomization up to 44 months ]
    ECOG Performance status is measured on 6-point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work; 2=Ambulatory (>50% of waking hours), capable of all selfcare, but unable to carry out any work activities; 3=Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4=Completely disabled, cannot carry on any selfcare, totally confined to bed or chair; 5=Dead.

  25. Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG) [ Time Frame: Randomization up to 44 months ]
    Change relative to baseline in electrocardiogram measured throughout study.

  26. Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Randomization up to 44 months ]
    Vital signs will include body temperature, systolic and diastolic blood pressure, and heart rate.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female participants 18 years or older.
  2. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with white blood cells [WBC] <20,000 per microliter [/mcL]) or low blast AML based on 1 of the following:

    French American British (FAB) Classifications:

    • Refractory anemia with excess blasts (RAEB) - defined as having 5% to 20% myeloblasts in the bone marrow.
    • CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.

    OR

    WHO Classifications:

    • RAEB 1 - defined as having 5% to 9% myeloblasts in the bone marrow.
    • RAEB 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
    • CMML 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
    • CMML 1 (Although CMML 1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these participants may enroll only if bone marrow blasts >=5%.
    • WHO defined AML with 20% to 30% myeloblasts in the bone marrow and <30% myeloblasts in peripheral blood who are deemed by the investigator to be appropriate for azacitidine based therapy.
  3. For MDS and CMML participants, prognostic risk category, based on the Revised International Prognostic Scoring System (IPSS R), of:

    • Very high (>6 points),
    • High (>4.5 to 6 points), or
    • Intermediate (>3 to 4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts.
  4. ECOG performance status of 0 to 2.
  5. Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug):

    • Albumin >2.7 g/dL.
    • Total bilirubin <upper limit of normal (ULN) except in participants with Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct bilirubin <=1.5*ULN of the direct bilirubin.
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5*ULN.
    • Creatinine clearance >=50 milliliter per minutes (mL/min).
    • Hb >8 g/dL. Participants may be transfused to achieve this value. Elevated indirect bilirubin due to post transfusion hemolysis is allowed.
  6. For CMML participants: WBC count <20,000/mcL before administration of the first dose of study drug on Cycle 1 Day 1; participants must have been off hydroxyurea for at least 1 week prior to WBC count assessment.
  7. Ability to undergo the study required bone marrow sample collection procedures.
  8. Suitable venous access for the study required blood sampling (that is, including pharmacokinetic (PK) and biomarker sampling).
  9. Female participants 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 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, or
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, 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 participants, even if surgically sterilized (that is, status postvasectomy), who:

    • Agree to practice effective barrier contraception during the entire study treatment period and 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 participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).
  10. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

Exclusion Criteria:

  1. Previous treatment with decitabine or azacitidine or other hypomethylating agent.
  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. Eligible for allogenic stem cell transplantation.
  4. Participants with MDS, CMML, or low blast AML, whose only site of disease is extramedullary, example, the skin.
  5. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures or could limit participant expected survival to less than 6 months.
  6. Treatment with any anti leukemic/anti MDS therapies (example, lenalidomide, cytarabine, anthracyclines, purine analogs) or with any investigational products within 14 days before the first dose of any study drug.
  7. Known hypersensitivity to mannitol.
  8. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
  9. Major surgery within 14 days before first dose or a scheduled surgery during study period; insertion of a venous access device (example, catheter, port) is not considered major surgery.
  10. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
  11. Life threatening illness unrelated to cancer.
  12. Prothrombin time (PT) or prolongation of the activated thromboplastin time (aPTT) >1.5 ULN or active uncontrolled coagulopathy or bleeding disorder.
  13. Known human immunodeficiency virus (HIV) seropositive.
  14. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Participants who have isolated positive hepatitis B core antibody (that is, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.
  15. Known hepatic cirrhosis or severe pre-existing hepatic impairment.
  16. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III or IV) and/or myocardial infarction within 6 months prior to first dose, or severe pulmonary hypertension. As an example, well controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.
  17. Treatment with strong cytochrome P450 (CYP) 3A inhibitors or inducers within 14 days before the first dose of study drug.
  18. Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 12 months before the first dose of any study drug, except for hydroxyurea.
  19. Female participants who are lactating and breast feeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.
  20. Female participants who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).
  21. Male participants who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02610777


  Show 59 Study Locations
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02610777     History of Changes
Other Study ID Numbers: Pevonedistat-2001
U1111-1169-6540 ( Registry Identifier: WHO )
2015-000221-37 ( EudraCT Number )
REec-2016-2145 ( Registry Identifier: REec )
Pevonedistat-2001CTID ( Other Identifier: Israel )
First Posted: November 20, 2015    Key Record Dates
Last Update Posted: November 19, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: "Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment."

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Drug Therapy

Additional relevant MeSH terms:
Syndrome
Leukemia
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myeloid
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Juvenile
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors