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

NCT04266795 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: Pevonedistat-20022019-003117-33U1111-1239-7581
• Study Type: interventional
• Target: 164
• Locations: 5 countries
• Sites: 57

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.

Conditions

Acute Myeloid Leukemia (AML)

Keywords

Drug Therapy

Outcome Measures

Primary Outcomes (1)

• 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.

  Up to 22 months

Secondary Outcomes (11)

• Overall Survival (OS)

  Up to 36 months

• Thirty-day Mortality Rate

  Day 30

• Sixty-day Mortality Rate

  Day 60

• Percentage of Participants With Complete Remission (CR)

  Up to 36 months

• Percentage of Participants With Composite Complete Remission (CCR)

  Up to 36 months

Study Arms (2)

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

ACTIVE COMPARATOR

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.

Drug: Venetoclax; Drug: Azacitidine

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

EXPERIMENTAL

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.

Drug: Pevonedistat; Drug: Venetoclax; Drug: Azacitidine

Interventions

Pevonedistat DRUG

Pevonedistat IV infusion.

Also known as: TAK-924, MLN4924

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

Venetoclax DRUG

Venetoclax tablets.

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

Azacitidine DRUG

Azacitidine IV or SC injection.

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Takeda: lead

Study Sites (57)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

UC San Diego Moores Cancer Center

La Jolla, California, 92093, United States

Location

UC Irvine Medical Center

Orange, California, 92868, United States

Location

University of Miami Miller School of Medicine

Miami, Florida, 33136, United States

Location

AdventHealth (Florida Hospital) - Transplant Institute

Orlando, Florida, 32804, United States

Location

Norton Cancer Institute - Suburban

Louisville, Kentucky, 40207, United States

Location

Tulane Medical Center

New Orleans, Louisiana, 70112, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

HCA Midwest Health - SCRI - PPDS

Kansas City, Missouri, 64132, United States

Location

Northwell Health Cancer Institute

Lake Success, New York, 11042, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029-6574, United States

Location

Stony Brook Medicine

Stony Brook, New York, 11794, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27514-4221, United States

Location

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

The University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

Avera Cancer Institute

Sioux Falls, South Dakota, 57105, United States

Location

Houston Methodist Cancer Center

Houston, Texas, 77030, United States

Location

Joe Arrington Cancer Research and Treatment Center

Lubbock, Texas, 79410, United States

Location

Intermountain LDS Hospital

Salt Lake City, Utah, 84143, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

West Virginia University Hospital

Morgantown, West Virginia, 26506, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

University of Alberta

Edmonton, Alberta, T6G 2G3, Canada

Location

Tom Baker Cancer Centre

Tom Baker Cancer Centre, Alberta, T2N 4N2, Canada

Location

London Health Sciences Centre

London, Ontario, N6A 5W9, Canada

Location

Ottawa Hospital

Ottawa, Ontario, K1H 8L6, Canada

Location

Hopital de L'enfant Jesus

Québec, Quebec, G1J 1Z4, Canada

Location

Centre Hospitalier Le Mans

Le Mans, Sarthe, 72000, France

Location

Hopital Avicenne

Bobigny, 93009, France

Location

Institut dHematologie de Basse Normandie

Caen, 14033, France

Location

CHU de Grenoble

Grenoble, 38043, France

Location

CHRU Lille

Lille, 59037, France

Location

CHRU Nantes

Nantes, 44093, France

Location

CHU de Nice

Nice, 06202, France

Location

Hopital Saint Antoine

Paris, 75012, France

Location

Hopital Saint Louis

Paris, 75475, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

CHRU de Poitiers La Miletrie

Poitiers, 86021, France

Location

EDOG - Institut Claudius Regaud - PPDS

Toulouse, 31059, France

Location

Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli

Reggio Calabria, Calabria, 89133, Italy

Location

ASST di Monza - Azienda Ospedaliera San Gerardo

Monza, Lombardy, 20900, Italy

Location

Istituto Clinico Humanitas

Rozzano, Milano, 20089, Italy

Location

Azienda Sanitaria Ospedaliera S Luigi Gonzaga

Orbassano, Piedmont, 10043, Italy

Location

Azienda Ospedaliera Citta della Salute e della Scienza di Torino

Turin, Piedmont, 10126, Italy

Location

Ospedale Santa Maria Della Misericordia Di Perugia

Perugia, Umbria, 06156, Italy

Location

Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi

Bologna, 40138, Italy

Location

Azienda Ospedaliera Universitaria Careggi

Florence, 50134, Italy

Location

Fondazione IRCCS Policlinico San Matteo di Pavia

Pavia, 27100, Italy

Location

Szpital Uniwersytecki w Krakowie

Krakow, Lesser Poland Voivodeship, 31-501, Poland

Location

MTZ Clinical Research Sp z o o

Warsaw, Masovian Voivodeship, 02-106, Poland

Location

Instytut Hematologii i Transfuzjologii

Warsaw, Masovian Voivodeship, 02-776, Poland

Location

Uniwersytecki Szpital Kliniczny w Bialymstoku

Bialystok, Podlaskie Voivodeship, 15-276, Poland

Location

Szpital Uniwersytecki Nr 2 im. Dr Jana Biziela w Bydgoszczy

Bydgoszcz, 85-168, Poland

Location

Uniwersyteckie Centrum Kliniczne

Gdansk, 80-952, Poland

Location

Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie

Lublin, 20-081, Poland

Location

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

Lodz, Łódź Voivodeship, 93-513, Poland

Location

Related Publications (1)

• 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.

  PMID: 39606906 DERIVED

Related Links

• To obtain more information about this study, click this link

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

pevonedistat; venetoclax; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 4, 2020
• First Posted: February 12, 2020
• Study Start: October 13, 2020
• Primary Completion: September 6, 2022
• Study Completion: October 6, 2025
• Last Updated: October 21, 2025
• Results First Posted: September 18, 2023

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• 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.

Locations

FR (12); PL (8); IT (9); US (23); CA (5)