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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)

NCT02610777

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • 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

Clinical Trial IDs

  • ORG STUDY ID: Pevonedistat-2001
  • SECONDARY ID: U1111-1169-6540
  • SECONDARY ID: 2015-000221-37
  • SECONDARY ID: REec-2016-2145
  • SECONDARY ID: Pevonedistat-2001CTID
  • NCT ID: NCT02610777

Conditions

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

Interventions

DrugSynonymsArms
AzacitidineAzacitidine
PevonedistatAzacitidine + Pevonedistat

Purpose

The purpose of this study is to evaluate the efficacy and safety of pevonedistat plus azacitidine versus single-agent azacitidine in participants with higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia and low-blast acute myelogenous leukemia.

Detailed Description

      The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to
      treat people with myelodysplastic syndromes, chronic myelomonocytic leukemia and low-blast
      acute myelogenous leukemia 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 117 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 69 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 (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).
    

Trial Arms

NameTypeDescriptionInterventions
AzacitidineActive ComparatorAzacitidine 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.
  • Azacitidine
Azacitidine + PevonedistatExperimentalAzacitidine 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.
  • Azacitidine
  • Pevonedistat

Eligibility 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

             Worl health organisation (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%-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 - 6 points), or

               -  Intermediate (>3 - 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. Eastern Cooperative Oncology Group (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).

               -  Hemoglobin >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 (eg, 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 (eg, 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-Free Survival (EFS)
Time Frame:From randomization until transformation to acute myeloid leukemia, disease progression or death due to any cause, up to 69 months
Safety Issue:
Description:EFS is defined as time from randomization until transformation to acute myeloid leukemia (AML) or death due to any cause whichever occurs first for participants with higher-risk myelodysplastic syndromes (HR MDS) or chronic myelomonocytic leukemia (CMML), or disease progression or relapse after CR or death due to any cause whichever occurs first for participants with low-blast AML. Transformation to AML is defined as a participant having 20% blasts in blood or marrow and increase of blast count by 50%. Disease progression for low blast-AML is defined as 1 of following: >50% increase in bone marrow blasts or circulating blasts from baseline value to >30% blasts; development of biopsy-proven extramedullary disease, or new sites of extramedullary leukemia. Relapse after CR is defined as a reappearance of leukemic blasts in the peripheral blood or >= 5% blasts in bone marrow not attributable to any other cause (eg, bone marrow regeneration after consolidation therapy).

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:From randomization until death, up to 69 months
Safety Issue:
Description: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 cutoff date, whichever is earlier.
Measure:Time to AML Transformation in HR MDS and CMML Participants
Time Frame:From randomization until transformation to AML, up to 69 months
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 Complete Remission (CR)
Time Frame:From randomization until CR, up to 69 months
Safety Issue:
Description: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).
Measure:Percentage of Participants With CR and Partial Remission (PR)
Time Frame:From randomization until CR and PR, up to 69 months
Safety Issue:
Description: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.
Measure:Percentage of Participants With Overall Response
Time Frame:From randomization until, CR, PR or hematologic improvement (HI), up to 69 months
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,PR/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:hb 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 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 /TTP <100*10^9/L;PR:all CR hematological values but>=50% decrease in bone marrow aspirate.
Measure:Duration of CR
Time Frame:From randomization until CR, up to 69 months
Safety Issue:
Description: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, neutroplhils 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).
Measure:Duration of CR and PR
Time Frame:From randomization until CR or PR, up to 69 months
Safety Issue:
Description: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.
Measure:Duration of Overall Response
Time Frame:From randomization until, CR, PR or HI, up to 69 months
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,PR/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.
Measure:Time to First CR or PR
Time Frame:From randomization until CR or PR, up to 69 months
Safety Issue:
Description: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.
Measure:Time to Subsequent Therapy
Time Frame:From randomization up to 69 months
Safety Issue:
Description: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.
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 69 months)
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: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 69 months
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 or death, up to 69 months
Safety Issue:
Description: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 (eg: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.
Measure: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 69 months)
Safety Issue:
Description: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 (eg, 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.
Measure:Number of Participants With Markedly Abnormal Clinical Laboratory Values
Time Frame:Randomization up to 69 months
Safety Issue:
Description:The number of participants with any markedly abnormal standard safety laboratory values will be collected throughout study.
Measure:Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status
Time Frame:Randomization up to 69 months
Safety Issue:
Description: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.
Measure:Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG)
Time Frame:Randomization up to 69 months
Safety Issue:
Description:Change relative to baseline in electrocardiogram measured throughout study.
Measure:Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Time Frame:Randomization up to 69 months
Safety Issue:
Description:Vital signs will include body temperature, systolic and diastolic blood pressure, and heart rate.
Measure:Six-Months Survival Rate
Time Frame:Month 6
Safety Issue:
Description:Six-month survival rate is defined as the percentage of participants who are alive six months after randomization.
Measure:One-Year Survival Rate
Time Frame:Month 12
Safety Issue:
Description:One -year survival rate is defined as the percentage of participants who are alive one year after randomization
Measure:Percentage of Participants With CR at Cycle 4
Time Frame:From randomization until CR, up to Cycle 4 (Month 5)
Safety Issue:
Description: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).
Measure:Percentage of Participants With CR and PR at Cycle 4
Time Frame:From randomization until CR and PR, up to Cycle 4 (Month 5)
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,PR/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.
Measure:Percentage of Participants With Overall Response at Cycle 4
Time Frame:From randomization until CR, PR or HI, up to Cycle 4 (Month 5)
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,PR/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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • Drug Therapy

Last Updated

January 31, 2017