Clinical Trials /

Triple Combination of Pevonedistat and Venetoclax Plus Azacitidine in Adults With Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy

NCT04266795

Description:

The purpose of this study is to determine whether the combination of pevonedistat + venetoclax + azacitidine improves event-free survival (EFS) compared with venetoclax + azacitidine in patients with newly diagnosed acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

Related Conditions:
  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising from Previous Myelodysplastic Syndrome
  • Secondary Acute Myeloid Leukemia
  • Therapy-Related Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT04266795

Trial Eligibility

Document

Title

  • Brief Title: Triple Combination of Pevonedistat and Venetoclax Plus Azacitidine in Adults With Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy
  • Official Title: A Randomized, Open-label, Controlled, Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults With Newly Diagnosed Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: Pevonedistat-2002
  • SECONDARY ID: 2019-003117-33
  • SECONDARY ID: U1111-1239-7581
  • NCT ID: NCT04266795

Conditions

  • Acute Myeloid Leukemia (AML)

Interventions

DrugSynonymsArms
PevonedistatTAK-924, MLN4924Arm A: Pevonedistat + Venetoclax + Azacitidine
VenetoclaxArm A: Pevonedistat + Venetoclax + Azacitidine
AzacitidineArm A: Pevonedistat + Venetoclax + Azacitidine

Purpose

The purpose of this study is to determine whether the combination of pevonedistat + venetoclax + azacitidine improves event-free survival (EFS) compared with venetoclax + azacitidine in patients with newly diagnosed acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.

Detailed Description

      The drug being tested in this study is called Pevonedistat. Pevonedistat is being tested to
      treat people who have AML. This study will compare the improvement in EFS in Arm A:
      pevonedistat + venetoclax + azacitidine combination arm group when compared with Arm B:
      venetoclax + azacitidine.

      The study will enroll approximately 150 patients. Participants will be randomly assigned in
      1:1 ratio to one of the two treatment groups in 28-day treatment cycles and which will remain
      disclosed to the patient and study doctor during the study:

        -  Pevonedistat 20 mg/m^2 + Venetoclax 400 mg (ramp-up dose, Cycle 1 only: 100-400mg) +
           Azacitidine 75 mg/m^2

        -  Venetoclax 400 mg (ramp-up dose, Cycle 1 only: 100-400 mg) + Azacitidine 75 mg/m^2

      This multi-center trial will be conducted worldwide. The overall time to participate in this
      study is approximately 4 years. 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 who discontinue study treatment without evidence of
      progressive disease (PD) will enter EFS follow-up or response follow-up (study visits every 3
      months) or overall survival follow-up (contacted every 3 months to document subsequent
      therapies and survival status).

Trial Arms

NameTypeDescriptionInterventions
Arm A: Pevonedistat + Venetoclax + AzacitidineExperimentalPevonedistat 20 mg/m^2 as a 60-minute intravenous (IV) infusion on Days 1, 3, and 5 in each 28-day cycle plus venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. If remission is confirmed in Cycle 1 or thereafter, venetoclax 400 mg can be administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 IV or subcutaneous (SC) dosing on Day 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle.
  • Pevonedistat
  • Venetoclax
  • Azacitidine
Arm B: Venetoclax + AzacitidineActive ComparatorVenetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. If remission is confirmed in Cycle 1 or thereafter, venetoclax 400 mg can be administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 IV or SC dosing on Days 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle.
  • Venetoclax
  • Azacitidine

Eligibility Criteria

        Inclusion Criteria:

          -  Has morphologically confirmed diagnosis of AML (World Health Organization [WHO]
             criteria 2008). Participants may have newly diagnosed primary de novo AML or secondary
             AML (sAML), defined as AML after myelodysplastic syndromes (MDS) or myeloproliferative
             neoplasm (MPN), or therapy-related AML (t-AML) following cytotoxic therapy, and/or
             radiotherapy for a malignant or nonmalignant disease.

          -  Is unfit for treatment with a standard Ara-C and anthracycline induction regimen due
             to age or co-morbidities defined by 1 of the following:

               -  ≥75 years of age. OR

               -  ≥18 to <75 years of age with at least one of the following:

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3.

          -  Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection
             fraction ≤50%, or chronic stable angina).

          -  Severe pulmonary disorder (e.g., carbon monoxide lung diffusion capacity ≤65% or
             forced expiratory volume in 1 second ≤65%).

          -  Creatinine clearance (CrCl) <45 mL/min (but ≥30 mL/min as part of general eligibility
             criteria).

          -  Hepatic disorder with total bilirubin >1.5 times the upper limit of the normal range
             (ULN).

          -  Has 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):

               -  Total bilirubin ≤1.5 times the ULN except in participants with Gilbert's
                  syndrome. Participants with Gilbert's syndrome may enroll with direct bilirubin
                  ≤3 times the ULN of the direct bilirubin. Elevated indirect bilirubin due to
                  posttransfusion hemolysis is allowed.

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 times
                  the ULN.

               -  Creatinine clearance (CrCl) ≥30 mL/min (calculated by the Modification of Diet in
                  Renal Disease [MDRD] Study equation).

               -  Albumin >2.7 g/dL.

          -  WBC count <25 × 10^9/L. Participants who are cytoreduced with leukapheresis or with
             hydroxyurea may be enrolled if they meet the eligibility criteria before starting
             therapy.

        Exclusion Criteria:

          -  Has history of MPN with BCR-ABL1 translocation or AML with BCR-ABL1 translocation.

          -  Has genetic diagnosis of acute promyelocytic leukemia.

          -  Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation.

          -  Has extramedullary AML without evidence of bone marrow involvement.

          -  Had prior treatment with hypomethylating agents for AML (hypomethylating agent
             treatment for prior MDS is not exclusionary).

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

          -  Had diagnosed or treated for another malignancy (except for adequately treated
             carcinoma in situ of any organ or nonmelanoma skin cancer) within 1 year before
             randomization or previously diagnosed with another malignancy and have any evidence of
             residual disease that may compromise the administration of pevonedistat, venetoclax or
             azacitidine. Prior MDS is also allowed, but the participant cannot have received
             treatment for MDS within 14 days before first dose of any study drug.

          -  Has a WBC count ≥25 × 10^9/L

          -  Has uncontrolled human immunodeficiency virus (HIV) infection. Note: Known HIV
             positive participants who meet the following criteria will be considered eligible:

               -  Cluster difference 4 (CD4) count >350 cells/mm^3.

               -  Undetectable viral load.

               -  Maintained on modern therapeutic regimens utilizing non-cytochrome P
                  (CYP)-interactive agents.

               -  No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic
                  infections.

          -  Participant is known to be positive for hepatitis B or C infection, with the exception
             of those with an undetectable viral load within 3 months (hepatitis B or C testing is
             not required for eligibility assessment).

          -  Has hepatic cirrhosis.

          -  Has uncontrolled coagulopathy or bleeding disorder.

          -  Has high blood pressure which cannot be controlled by standard treatments.

          -  Has prolonged rate QTc interval ≥500 msec, calculated according to institutional
             guidelines.

          -  Has left ventricular ejection fraction (LVEF) <40%, based on echocardiogram or
             multigated acquisition (MUGA) scan at screening (data to be available within last 3
             months of screening).

          -  As infection is a common feature of AML, participants with active infection are
             permitted to enroll provided that the infection is under control and no signs of
             systemic inflammatory response beyond low grade fever that makes participant
             clinically unstable in the opinion of the investigator. Participants with uncontrolled
             infection shall not be enrolled until infection is treated and brought under control.
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:Up to 48 months
Safety Issue:
Description:EFS is defined as time from study randomization to date of failure to achieve complete remission (CR)/CR with incomplete blood count recovery (CRi), relapse from CR/CRi, or death. Assessments of disease response based on criteria: European Leukemia Net (ELN) 2017 guidelines. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC)≥1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]). For participants who achieved CR/CRi, if relapse is not observed by time of analysis, will be censored at the date of last disease assessment. If fail to achieve CR/CRi, date of treatment failure will be set on day of randomization. Data for participants without disease assessments censored at date of randomization (except who died before assessment).

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to 48 months
Safety Issue:
Description:OS is defined as time from randomization to death from any cause. Participants without documentation of death at the time of analysis will be censored at the date last known to be alive.
Measure:Six-month Survival Rate
Time Frame:Month 6
Safety Issue:
Description:Six-month survival rate is defined as the Kaplan-Meier (K-M) estimate of survival rate at 6-month.
Measure:One-year Survival Rate
Time Frame:Month 12
Safety Issue:
Description:One-year survival rate is defined as the K-M estimate of survival rate at 1-year.
Measure:Two-year Survival Rate
Time Frame:Month 24
Safety Issue:
Description:Two-year survival rate is defined as the K-M estimate of survival rate at 2-year.
Measure:Thirty-day Mortality Rate
Time Frame:Day 30
Safety Issue:
Description:Mortality rate is defined as percentage of participants who survive at most 30 days from the first dose of study drug.
Measure:Sixty-day Mortality Rate
Time Frame:Day 60
Safety Issue:
Description:Mortality rate is defined as percentage of participants who survive at most 60 days from the first dose of study drug.
Measure:Percentage of Participants with Complete Remission (CR)
Time Frame:Up to 48 months
Safety Issue:
Description:CR rate is defined as the percentage of participants who achieve the CR as evaluated by the independent review committee (IRC). Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL).
Measure:Percentage of Participants with Composite Complete Remission (CCR)
Time Frame:Up to 48 months
Safety Issue:
Description:CCR rate is defined as the percentage of participants who achieve the CR + CRi as evaluated by the IRC. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]).
Measure:Overall Response Rate (ORR)
Time Frame:Up to 48 months
Safety Issue:
Description:ORR is defined as the percentage of participants who achieve the CR + CRi + Partial Remission (PR) as evaluated by the IRC. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]). PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%.
Measure:Percentage of Participants with CR + CRh
Time Frame:Up to 48 months
Safety Issue:
Description:CR + CRh rate is defined as the percentage of participants who achieve the CR + CRh as evaluated by the IRC. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). CRh is defined as bone marrow with <5% blasts, peripheral blood neutrophil count >0.5×10^3/µL and peripheral blood platelet count >0.5×10^5/µL.
Measure:Percentage of Participants with Leukemia Response
Time Frame:Up to 48 months
Safety Issue:
Description:Leukemia response rate is defined as the percentage of participants who achieve the CR + CRi + PR + morphological leukemia-free state [MLFS, marrow CR (mCR)]) as evaluated by the IRC. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥ 1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]). PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%. MLFS is defined as bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required.
Measure:Duration of CR
Time Frame:Up to 48 months
Safety Issue:
Description:Duration of CR is defined as the time from randomization to CR and will be summarized descriptively using the K-M method based on the responders. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥ 1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL).
Measure:Duration of CRi
Time Frame:Up to 48 months
Safety Issue:
Description:Duration of CRi is defined as the time from randomization to CRi and will be summarized descriptively using the K-M method based on the responders. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]).
Measure:Duration of CCR
Time Frame:Up to 48 months
Safety Issue:
Description:Duration of CCR is defined as the time from randomization to CCR and will be summarized descriptively using the K-M method based on the responders. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CCR is defined as the percentage of participants who achieve the CR + CRi as evaluated by the IRC. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥ 1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]).
Measure:Percentage of Participants who Failed to Achieve CR or CRi
Time Frame:At completion of 6 treatment cycles, relapse from CR/CRi or death from any cause, whichever occurs first
Safety Issue:
Description:CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥ 1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]).
Measure:Duration of ORR
Time Frame:Up to 48 months
Safety Issue:
Description:Duration of ORR is defined as the time from randomization to ORR and will be summarized descriptively using the K-M method based on the responders. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. ORR is defined as the percentage of participants who achieve the CR + CRi + PR. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥ 1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]). PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%.
Measure:Time to First CR
Time Frame:Up to 48 months
Safety Issue:
Description:Time to first CR is defined as the time from randomization until the first documented CR and will be analyzed using the K-M method. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥ 1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL).
Measure:Time to First CRi
Time Frame:Up to 48 months
Safety Issue:
Description:Time to first CRi is defined as the time from randomization until the first documented CRi and will be analyzed using the K-M method. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]).
Measure:Time to First PR
Time Frame:Up to 48 months
Safety Issue:
Description:Time to first PR is defined as the time from randomization until the first documented PR and will be analyzed using the K-M method. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%.
Measure:Time to Relapse from CR/CRi or Death
Time Frame:Up to 48 months
Safety Issue:
Description:Time to relapse is defined as the time from randomization until relapse from CR/CRi or death, whichever occurs first and will be analyzed using the K-M method. Assessments of disease response are based on the criteria outlined in the ELN 2017 guidelines. CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC≥1.0×10^9/L (1000/µL); platelet count≥100×10^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (<1.0×10^9/L [1000/µL]) or thrombocytopenia (<100×10^9/L [100,000/µL]).
Measure:Health-Related Quality of Life (HRQOL) Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ)-C30 Scale
Time Frame:Up to 48 months
Safety Issue:
Description:EORTC-QLQ-C30 scale is used to assess HRQOL in cancer participants and contains 30 items which incorporates 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 quality of life (QOL)/health status scale. Most items have 4 response levels (1=not at all [best] to 4=very much [worst]), with 2 questions relying on a 7-point numeric rating scale (1=very poor [worst] to 7=excellent [best]). Supplemental items on symptoms (7 items) and functional impacts (3 items) from the EORTC item are included. The supplemental 10 items have 4 response levels (1=not at all to 4=very much). Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status scale, higher scores represent better HRQOL; whereas for the symptom scales lower scores represent better HRQOL.
Measure:HRQOL Measured by EuroQoL Five Dimensions Five Levels (EQ 5D-5L) Scale
Time Frame:Up to 48 months
Safety Issue:
Description:EQ-5D-5L is a self-administered preference-based measure of health status suitable for calculating quality-adjusted life-years (QALYs) to inform economic evaluations. EQ-5D-5L includes 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and 5 response levels for each domain (no problems, slight problems, moderate problems, severe problems, and extreme problems). Scores ranges from best (100) to worst (0).
Measure:Plasma Concentration of Pevonedistat
Time Frame:At multiple time points pre-dose and post-dose on Days 1, 3 and 5 in Cycle 1 and post-dose on Day 1 in Cycle 2 and 4
Safety Issue:
Description:
Measure:Percentage of Participants with Red Blood Cells (RBCs) and/or Platelet Transfusion Independence
Time Frame:Up to 48 months
Safety Issue:
Description:A participant is called as RBC and/or platelet-transfusion independent if he/she receives no RBC and/or platelet transfusions for a period of at least 8 weeks. Rate of RBC and/or platelet-transfusion independence is defined as percentage of participants who become RBC and/or platelet transfusion independent divided by the percentage of participants who are RBC and/or platelet transfusion dependent at baseline.
Measure:Percentage of Participants with Hospitalization
Time Frame:Up to 48 months
Safety Issue:
Description:Hospitalization rate is defined as the ratio of the number of participants who have hospital admission(s) related to AML over the total number of participants in each of the study treatment arms.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Takeda

Trial Keywords

  • Drug Therapy

Last Updated

May 10, 2021