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

NCT ID: NCT04266795

Last Updated: 2025-10-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 164 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-13
• Study Completion Date: 2025-10-06

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.

Conditions

Acute Myeloid Leukemia (AML)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

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.

Group Type: ACTIVE_COMPARATOR

Venetoclax

Intervention Type: DRUG

Venetoclax tablets.

Azacitidine

Intervention Type: DRUG

Azacitidine IV or SC injection.

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

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.

Group Type: EXPERIMENTAL

Pevonedistat

Intervention Type: DRUG

Pevonedistat IV infusion.

Venetoclax

Intervention Type: DRUG

Venetoclax tablets.

Azacitidine

Intervention Type: DRUG

Azacitidine IV or SC injection.

Interventions

Pevonedistat

Pevonedistat IV infusion.

Intervention Type: DRUG

Venetoclax

Venetoclax tablets.

Intervention Type: DRUG

Azacitidine

Azacitidine IV or SC injection.

Intervention Type: DRUG

Other Intervention Names

TAK-924; MLN4924

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Takeda

Locations

Banner MD Anderson Cancer Center

Gilbert, Arizona, United States

UC San Diego Moores Cancer Center

La Jolla, California, United States

UC Irvine Medical Center

Orange, California, United States

University of Miami Miller School of Medicine

Miami, Florida, United States

AdventHealth (Florida Hospital) - Transplant Institute

Orlando, Florida, United States

Norton Cancer Institute - Suburban

Louisville, Kentucky, United States

Tulane Medical Center

New Orleans, Louisiana, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

HCA Midwest Health - SCRI - PPDS

Kansas City, Missouri, United States

Northwell Health Cancer Institute

Lake Success, New York, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Stony Brook Medicine

Stony Brook, New York, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

The University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Rhode Island Hospital

Providence, Rhode Island, United States

Avera Cancer Institute

Sioux Falls, South Dakota, United States

Houston Methodist Cancer Center

Houston, Texas, United States

Joe Arrington Cancer Research and Treatment Center

Lubbock, Texas, United States

Intermountain LDS Hospital

Salt Lake City, Utah, United States

University of Virginia Health System

Charlottesville, Virginia, United States

West Virginia University Hospital

Morgantown, West Virginia, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

University of Alberta

Edmonton, Alberta, Canada

Tom Baker Cancer Centre

Tom Baker Cancer Centre, Alberta, Canada

London Health Sciences Centre

London, Ontario, Canada

Ottawa Hospital

Ottawa, Ontario, Canada

Hopital de L'enfant Jesus

Québec, Quebec, Canada

Centre Hospitalier Le Mans

Le Mans, Sarthe, France

Hopital Avicenne

Bobigny, , France

Institut dHematologie de Basse Normandie

Caen, , France

CHU de Grenoble

Grenoble, , France

CHRU Lille

Lille, , France

CHRU Nantes

Nantes, , France

CHU de Nice

Nice, , France

Hopital Saint Antoine

Paris, , France

Hopital Saint Louis

Paris, , France

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

CHRU de Poitiers La Miletrie

Poitiers, , France

EDOG - Institut Claudius Regaud - PPDS

Toulouse, , France

Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli

Reggio Calabria, Calabria, Italy

ASST di Monza - Azienda Ospedaliera San Gerardo

Monza, Lombardy, Italy

Istituto Clinico Humanitas

Rozzano, Milano, Italy

Azienda Sanitaria Ospedaliera S Luigi Gonzaga

Orbassano, Piedmont, Italy

Azienda Ospedaliera Citta della Salute e della Scienza di Torino

Turin, Piedmont, Italy

Ospedale Santa Maria Della Misericordia Di Perugia

Perugia, Umbria, Italy

Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi

Bologna, , Italy

Azienda Ospedaliera Universitaria Careggi

Florence, , Italy

Fondazione IRCCS Policlinico San Matteo di Pavia

Pavia, , Italy

Szpital Uniwersytecki w Krakowie

Krakow, Lesser Poland Voivodeship, Poland

MTZ Clinical Research Sp z o o

Warsaw, Masovian Voivodeship, Poland

Instytut Hematologii i Transfuzjologii

Warsaw, Masovian Voivodeship, Poland

Uniwersytecki Szpital Kliniczny w Bialymstoku

Bialystok, Podlaskie Voivodeship, Poland

Szpital Uniwersytecki Nr 2 im. Dr Jana Biziela w Bydgoszczy

Bydgoszcz, , Poland

Uniwersyteckie Centrum Kliniczne

Gdansk, , Poland

Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie

Lublin, , Poland

Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi

Lodz, Łódź Voivodeship, Poland

Countries

United States; Canada; France; Italy; Poland

References

Short NJ, Wierzbowska A, Cluzeau T, Laribi K, Recher C, Czyz J, Ochrem B, Ades L, Gallego-Hernanz MP, Heiblig M, Audisio E, Zarzycka E, Li S, Ferenc N, Yeh T, Faller DV, Sedarati F, Papayannidis C. Azacitidine and venetoclax with or without pevonedistat in patients with newly diagnosed acute myeloid leukemia. Leuk Lymphoma. 2025 Mar;66(3):458-468. doi: 10.1080/10428194.2024.2431878. Epub 2024 Nov 28.

Reference Type: DERIVED

PMID: 39606906 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.takeda.com/study-detail/5f6b603d4db2bf003ab4a389?idFilter=%5B%22Pevonedistat-2002%22%5D

To obtain more information about this study, click this link

Other Identifiers

2019-003117-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1239-7581

Identifier Type: REGISTRY

Identifier Source: secondary_id

Pevonedistat-2002

Identifier Type: -

Identifier Source: org_study_id