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A Study of Pevonedistat and Venetoclax Combined With Azacitidine to Treat Acute Myeloid Leukemia (AML) in Adults Unable to Receive Intensive Chemotherapy (PEVENAZA)

Primary Purpose

Acute Myeloid Leukemia (AML)

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Pevonedistat
Venetoclax
Azacitidine
Sponsored by
Takeda
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia (AML) focused on measuring Drug Therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 arabinosylcytosine (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.
  • White blood cell (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 multi gated 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.

Sites / Locations

  • Banner MD Anderson Cancer Center
  • UC San Diego Moores Cancer Center
  • UC Irvine Medical Center
  • University of Miami Miller School of Medicine
  • AdventHealth (Florida Hospital) - Transplant Institute
  • Norton Cancer Institute - Suburban
  • Tulane Medical Center
  • Massachusetts General Hospital
  • HCA Midwest Health - SCRI - PPDS
  • Northwell Health Cancer Institute
  • Icahn School of Medicine at Mount Sinai
  • Stony Brook Medicine
  • University of North Carolina at Chapel Hill
  • University Hospitals Cleveland Medical Center
  • The University of Oklahoma Health Sciences Center
  • Rhode Island Hospital
  • Avera Cancer Institute
  • Houston Methodist Cancer Center
  • Joe Arrington Cancer Research and Treatment Center
  • Intermountain LDS Hospital
  • University of Virginia Health System
  • West Virginia University Hospital
  • Medical College of Wisconsin
  • University of Alberta
  • Tom Baker Cancer Centre
  • London Health Sciences Centre
  • Ottawa Hospital
  • Hopital de L'enfant Jesus
  • Centre Hospitalier Le Mans
  • Hopital Avicenne
  • Institut dHematologie de Basse Normandie
  • CHU de Grenoble
  • CHRU Lille
  • CHRU Nantes
  • CHU de Nice
  • Hopital Saint Antoine
  • Hopital Saint Louis
  • Centre Hospitalier Lyon Sud
  • CHRU de Poitiers La Miletrie
  • EDOG - Institut Claudius Regaud - PPDS
  • Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli
  • ASST di Monza - Azienda Ospedaliera San Gerardo
  • Istituto Clinico Humanitas
  • Azienda Sanitaria Ospedaliera S Luigi Gonzaga
  • Azienda Ospedaliera Citta della Salute e della Scienza di Torino
  • Ospedale Santa Maria Della Misericordia Di Perugia
  • Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi
  • Azienda Ospedaliera Universitaria Careggi
  • Fondazione IRCCS Policlinico San Matteo di Pavia
  • Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
  • Szpital Uniwersytecki w Krakowie
  • MTZ Clinical Research Sp z o o
  • Instytut Hematologii i Transfuzjologii
  • Uniwersytecki Szpital Kliniczny w Bialymstoku
  • Szpital Uniwersytecki Nr 2 im. Dr Jana Biziela w Bydgoszczy
  • Uniwersyteckie Centrum Kliniczne
  • Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2

Pevonedistat 20 mg/m^2 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2

Arm Description

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 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 intravenous (IV) or subcutaneous (SC) dosing on Days 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.

Pevonedistat 20 mg/m^2 as a 60-minute 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 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 IV or SC dosing on Day 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.

Outcomes

Primary Outcome Measures

Event-Free Survival (EFS)
EFS was 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 was 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 was 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, was censored at the date of last disease assessment. If failed to achieve CR/CRi, date of treatment failure was set on day of randomization.

Secondary Outcome Measures

Overall Survival (OS)
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.
Thirty-day Mortality Rate
Mortality rate is defined as percentage of participants who survive at most 30 days from the first dose of study drug.
Sixty-day Mortality Rate
Mortality rate is defined as percentage of participants who survive at most 60 days from the first dose of study drug.
Percentage of Participants With Complete Remission (CR)
CR rate is defined as the percentage of participants who achieve the CR as evaluated by the investigator. 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).
Percentage of Participants With Composite Complete Remission (CCR)
CCR rate is defined as the percentage of participants who achieve the CR + CRi as evaluated by the investigator. 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]).
Overall Response Rate (ORR)
ORR is defined as the percentage of participants who achieve the CR + CRi + Partial Remission (PR) as evaluated by the investigator. 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%.
Percentage of Participants With CR + CRh
CR + CRh rate is defined as the percentage of participants who achieve the CR + CRh as evaluated by the investigator. 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.
Percentage of Participants With Leukemia Response
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 investigator. 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.
Duration of CR and CRi
Duration of CR and CRi is defined as the time from first documentation of CR or CRi to the date of first documentation of PD or relapse from CR or 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. 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]).
Time to First CR, CRi and PR
Time to first CR, CRi, and PR is defined as the time from randomization until the first documented CR, CRi or PR, 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]). 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%.
Plasma Concentration of Pevonedistat

Full Information

First Posted
February 4, 2020
Last Updated
September 22, 2023
Sponsor
Takeda
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1. Study Identification

Unique Protocol Identification Number
NCT04266795
Brief Title
A Study of Pevonedistat and Venetoclax Combined With Azacitidine to Treat Acute Myeloid Leukemia (AML) in Adults Unable to Receive Intensive Chemotherapy
Acronym
PEVENAZA
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 13, 2020 (Actual)
Primary Completion Date
September 6, 2022 (Actual)
Study Completion Date
January 5, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Takeda

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The main aim is to see how the combination of pevonedistat + venetoclax + azacitidine compares to venetoclax + azacitidine in adults recently diagnosed with AML who are unable to be treated with intensive chemotherapy. Participants will receive either pevonedistat + venetoclax + azacitidine or venetoclax + azacitidine in 28-day treatment cycles. Bone marrow samples (biopsy) will be collected throughout the study. Pevonedistat will be given as an intravenous (IV) infusion and Azacitidine will be given through IV or subcutaneous (under the skin). Study treatments may continue as long as the participant is receiving benefit from it. Participants may choose to stop treatment at any time.
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 164 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 3 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia (AML)
Keywords
Drug Therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
164 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2
Arm Type
Active Comparator
Arm Description
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 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 intravenous (IV) or subcutaneous (SC) dosing on Days 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.
Arm Title
Pevonedistat 20 mg/m^2 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2
Arm Type
Experimental
Arm Description
Pevonedistat 20 mg/m^2 as a 60-minute 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 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m^2 IV or SC dosing on Day 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.
Intervention Type
Drug
Intervention Name(s)
Pevonedistat
Other Intervention Name(s)
TAK-924, MLN4924
Intervention Description
Pevonedistat IV infusion.
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Intervention Description
Venetoclax tablets.
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
Azacitidine IV or SC injection.
Primary Outcome Measure Information:
Title
Event-Free Survival (EFS)
Description
EFS was 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 was 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 was 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, was censored at the date of last disease assessment. If failed to achieve CR/CRi, date of treatment failure was set on day of randomization.
Time Frame
Up to 22 months
Secondary Outcome Measure Information:
Title
Overall Survival (OS)
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.
Time Frame
Up to 36 months
Title
Thirty-day Mortality Rate
Description
Mortality rate is defined as percentage of participants who survive at most 30 days from the first dose of study drug.
Time Frame
Day 30
Title
Sixty-day Mortality Rate
Description
Mortality rate is defined as percentage of participants who survive at most 60 days from the first dose of study drug.
Time Frame
Day 60
Title
Percentage of Participants With Complete Remission (CR)
Description
CR rate is defined as the percentage of participants who achieve the CR as evaluated by the investigator. 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).
Time Frame
Up to 36 months
Title
Percentage of Participants With Composite Complete Remission (CCR)
Description
CCR rate is defined as the percentage of participants who achieve the CR + CRi as evaluated by the investigator. 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]).
Time Frame
Up to 36 months
Title
Overall Response Rate (ORR)
Description
ORR is defined as the percentage of participants who achieve the CR + CRi + Partial Remission (PR) as evaluated by the investigator. 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%.
Time Frame
Up to 36 months
Title
Percentage of Participants With CR + CRh
Description
CR + CRh rate is defined as the percentage of participants who achieve the CR + CRh as evaluated by the investigator. 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.
Time Frame
Up to 36 months
Title
Percentage of Participants With Leukemia Response
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 investigator. 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.
Time Frame
Up to 36 months
Title
Duration of CR and CRi
Description
Duration of CR and CRi is defined as the time from first documentation of CR or CRi to the date of first documentation of PD or relapse from CR or 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. 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]).
Time Frame
Up to 36 months
Title
Time to First CR, CRi and PR
Description
Time to first CR, CRi, and PR is defined as the time from randomization until the first documented CR, CRi or PR, 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]). 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%.
Time Frame
Up to 36 months
Title
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 Cycles 2 and 4 (cycle length= 28 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 arabinosylcytosine (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. White blood cell (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 multi gated 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Takeda
Official's Role
Study Director
Facility Information:
Facility Name
Banner MD Anderson Cancer Center
City
Gilbert
State/Province
Arizona
ZIP/Postal Code
85234
Country
United States
Facility Name
UC San Diego Moores Cancer Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
UC Irvine Medical Center
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
University of Miami Miller School of Medicine
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
AdventHealth (Florida Hospital) - Transplant Institute
City
Orlando
State/Province
Florida
ZIP/Postal Code
32804
Country
United States
Facility Name
Norton Cancer Institute - Suburban
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40207
Country
United States
Facility Name
Tulane Medical Center
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
HCA Midwest Health - SCRI - PPDS
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64132
Country
United States
Facility Name
Northwell Health Cancer Institute
City
Lake Success
State/Province
New York
ZIP/Postal Code
11042
Country
United States
Facility Name
Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029-6574
Country
United States
Facility Name
Stony Brook Medicine
City
Stony Brook
State/Province
New York
ZIP/Postal Code
11794
Country
United States
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514-4221
Country
United States
Facility Name
University Hospitals Cleveland Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
The University of Oklahoma Health Sciences Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Rhode Island Hospital
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02903
Country
United States
Facility Name
Avera Cancer Institute
City
Sioux Falls
State/Province
South Dakota
ZIP/Postal Code
57105
Country
United States
Facility Name
Houston Methodist Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Joe Arrington Cancer Research and Treatment Center
City
Lubbock
State/Province
Texas
ZIP/Postal Code
79410
Country
United States
Facility Name
Intermountain LDS Hospital
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84143
Country
United States
Facility Name
University of Virginia Health System
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States
Facility Name
West Virginia University Hospital
City
Morgantown
State/Province
West Virginia
ZIP/Postal Code
26506
Country
United States
Facility Name
Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Facility Name
University of Alberta
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2G3
Country
Canada
Facility Name
Tom Baker Cancer Centre
City
Tom Baker Cancer Centre
State/Province
Alberta
ZIP/Postal Code
T2N 4N2
Country
Canada
Facility Name
London Health Sciences Centre
City
London
State/Province
Ontario
ZIP/Postal Code
N6A 5W9
Country
Canada
Facility Name
Ottawa Hospital
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H 8L6
Country
Canada
Facility Name
Hopital de L'enfant Jesus
City
Quebec City
State/Province
Quebec
ZIP/Postal Code
G1J 1Z4
Country
Canada
Facility Name
Centre Hospitalier Le Mans
City
Le Mans
State/Province
Sarthe
ZIP/Postal Code
72000
Country
France
Facility Name
Hopital Avicenne
City
Bobigny
ZIP/Postal Code
93009
Country
France
Facility Name
Institut dHematologie de Basse Normandie
City
Caen
ZIP/Postal Code
14033
Country
France
Facility Name
CHU de Grenoble
City
Grenoble
ZIP/Postal Code
38043
Country
France
Facility Name
CHRU Lille
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
CHRU Nantes
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
CHU de Nice
City
Nice
ZIP/Postal Code
06202
Country
France
Facility Name
Hopital Saint Antoine
City
Paris
ZIP/Postal Code
75012
Country
France
Facility Name
Hopital Saint Louis
City
Paris
ZIP/Postal Code
75475
Country
France
Facility Name
Centre Hospitalier Lyon Sud
City
Pierre Benite
ZIP/Postal Code
69495
Country
France
Facility Name
CHRU de Poitiers La Miletrie
City
Poitiers
ZIP/Postal Code
86021
Country
France
Facility Name
EDOG - Institut Claudius Regaud - PPDS
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli
City
Reggio Calabria
State/Province
Calabria
ZIP/Postal Code
89133
Country
Italy
Facility Name
ASST di Monza - Azienda Ospedaliera San Gerardo
City
Monza
State/Province
Lombardia
ZIP/Postal Code
20900
Country
Italy
Facility Name
Istituto Clinico Humanitas
City
Rozzano
State/Province
Milano
ZIP/Postal Code
20089
Country
Italy
Facility Name
Azienda Sanitaria Ospedaliera S Luigi Gonzaga
City
Orbassano
State/Province
Piemonte
ZIP/Postal Code
10043
Country
Italy
Facility Name
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
City
Torino
State/Province
Piemonte
ZIP/Postal Code
10126
Country
Italy
Facility Name
Ospedale Santa Maria Della Misericordia Di Perugia
City
Perugia
State/Province
Umbria
ZIP/Postal Code
06156
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria Careggi
City
Firenze
ZIP/Postal Code
50134
Country
Italy
Facility Name
Fondazione IRCCS Policlinico San Matteo di Pavia
City
Pavia
ZIP/Postal Code
27100
Country
Italy
Facility Name
Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
City
Lodz
State/Province
Lodzkie
ZIP/Postal Code
93-513
Country
Poland
Facility Name
Szpital Uniwersytecki w Krakowie
City
Krakow
State/Province
Malopolskie
ZIP/Postal Code
31-501
Country
Poland
Facility Name
MTZ Clinical Research Sp z o o
City
Warszawa
State/Province
Mazowieckie
ZIP/Postal Code
02-106
Country
Poland
Facility Name
Instytut Hematologii i Transfuzjologii
City
Warszawa
State/Province
Mazowieckie
ZIP/Postal Code
02-776
Country
Poland
Facility Name
Uniwersytecki Szpital Kliniczny w Bialymstoku
City
Bialystok
State/Province
Podlaskie
ZIP/Postal Code
15-276
Country
Poland
Facility Name
Szpital Uniwersytecki Nr 2 im. Dr Jana Biziela w Bydgoszczy
City
Bydgoszcz
ZIP/Postal Code
85-168
Country
Poland
Facility Name
Uniwersyteckie Centrum Kliniczne
City
Gdansk
ZIP/Postal Code
80-952
Country
Poland
Facility Name
Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie
City
Lublin
ZIP/Postal Code
20-081
Country
Poland

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
IPD Sharing Access Criteria
IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
IPD Sharing URL
https://vivli.org/ourmember/takeda/
Links:
URL
https://clinicaltrials.takeda.com/study-detail/5f6b603d4db2bf003ab4a389?idFilter=%5B%22Pevonedistat-2002%22%5D
Description
To obtain more information about this study, click this link

Learn more about this trial

A Study of Pevonedistat and Venetoclax Combined With Azacitidine to Treat Acute Myeloid Leukemia (AML) in Adults Unable to Receive Intensive Chemotherapy

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