Acute Myeloid Leukemia (AML)Phase 2PEVENAZANCT04266795
A Study of Pevonedistat and Venetoclax Combined With Azacitidine to Treat Acute Myeloid Leukemia (AML) in Adults Unable to Receive Intensive Chemotherapy
A Phase 2 study testing Pevonedistat, Venetoclax and Azacitidine in people with Acute Myeloid Leukemia (AML), run by Takeda at 57 sites in 5 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Myeloid Leukemia (AML)
- What is being tested?
- Pevonedistat, Venetoclax and Azacitidine
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 164 participants
- Where
- 57 sitesin 5 countries
- Study dates
- 13 Oct 2020to 6 Oct 2025
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
57 sites in 5 countries.
57 sites in 5 countries
United States23 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27514-4221
University of Virginia Health System
Charlottesville, Virginia, 22908
University Hospitals Cleveland Medical Center
Cleveland, Ohio, 44106
Banner MD Anderson Cancer Center
Gilbert, Arizona, 85234
Houston Methodist Cancer Center
Houston, Texas, 77030
HCA Midwest Health - SCRI - PPDS
Kansas City, Missouri, 64132
UC San Diego Moores Cancer Center
La Jolla, California, 92093
Northwell Health Cancer Institute
Lake Success, New York, 11042
Norton Cancer Institute - Suburban
Louisville, Kentucky, 40207
Joe Arrington Cancer Research and Treatment Center
Lubbock, Texas, 79410
University of Miami Miller School of Medicine
Miami, Florida, 33136
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
West Virginia University Hospital
Morgantown, West Virginia, 26506
Tulane Medical Center
New Orleans, Louisiana, 70112
Icahn School of Medicine at Mount Sinai
New York, New York, 10029-6574
The University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
UC Irvine Medical Center
Orange, California, 92868
AdventHealth (Florida Hospital) - Transplant Institute
Orlando, Florida, 32804
Rhode Island Hospital
Providence, Rhode Island, 02903
Intermountain LDS Hospital
Salt Lake City, Utah, 84143
Avera Cancer Institute
Sioux Falls, South Dakota, 57105
Stony Brook Medicine
Stony Brook, New York, 11794
France12 sites
Hopital Avicenne
Bobigny, 93009
Institut dHematologie de Basse Normandie
Caen, 14033
CHU de Grenoble
Grenoble, 38043
Centre Hospitalier Le Mans
Le Mans, Sarthe, 72000
CHRU Lille
Lille, 59037
CHRU Nantes
Nantes, 44093
CHU de Nice
Nice, 06202
Hopital Saint Antoine
Paris, 75012
Hopital Saint Louis
Paris, 75475
Centre Hospitalier Lyon Sud
Pierre-Bénite, 69495
CHRU de Poitiers La Miletrie
Poitiers, 86021
EDOG - Institut Claudius Regaud - PPDS
Toulouse, 31059
Italy9 sites
Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi
Bologna, 40138
Azienda Ospedaliera Universitaria Careggi
Florence, 50134
ASST di Monza - Azienda Ospedaliera San Gerardo
Monza, Lombardy, 20900
Azienda Sanitaria Ospedaliera S Luigi Gonzaga
Orbassano, Piedmont, 10043
Fondazione IRCCS Policlinico San Matteo di Pavia
Pavia, 27100
Ospedale Santa Maria Della Misericordia Di Perugia
Perugia, Umbria, 06156
Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli
Reggio Calabria, Calabria, 89133
Istituto Clinico Humanitas
Rozzano, Milano, 20089
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
Turin, Piedmont, 10126
Poland8 sites
Uniwersytecki Szpital Kliniczny w Bialymstoku
Bialystok, Podlaskie Voivodeship, 15-276
Szpital Uniwersytecki Nr 2 im. Dr Jana Biziela w Bydgoszczy
Bydgoszcz, 85-168
Uniwersyteckie Centrum Kliniczne
Gdansk, 80-952
Szpital Uniwersytecki w Krakowie
Krakow, Lesser Poland Voivodeship, 31-501
Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
Lodz, Łódź Voivodeship, 93-513
Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie
Lublin, 20-081
MTZ Clinical Research Sp z o o
Warsaw, Masovian Voivodeship, 02-106
Instytut Hematologii i Transfuzjologii
Warsaw, Masovian Voivodeship, 02-776
Canada5 sites
Tom Baker Cancer Centre
Calgary, Alberta, T2N 4N2
University of Alberta
Edmonton, Alberta, T6G 2G3
London Health Sciences Centre
London, Ontario, N6A 5W9
Ottawa Hospital
Ottawa, Ontario, K1H 8L6
Hopital de L'enfant Jesus
Québec, Quebec, G1J 1Z4
About this study
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
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.
Read the 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 participants. 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 participant 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)
- Being tested
- Pevonedistat, Venetoclax, Azacitidine
- Keywords
- Drug Therapy
- Medical subject headings
- Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PevonedistatDrug
Also called TAK-924, MLN4924
Pevonedistat IV infusion.
VenetoclaxDrug
Venetoclax tablets.
AzacitidineDrug
Azacitidine IV or SC injection.
| Study group | Role | What they receive |
|---|---|---|
| Venetoclax + Azacitidine | Active comparator | Participants received venetoclax 100 milligram (mg) tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Days 3 through 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 Days 1 through 21 or 28 as per Investigator's discretion. In addition, participants received azacitidine 75 milligrams per square meter (mg/m^2) intravenous (IV) or subcutaneous (SC) dosing on Days 1 through 7 or Days 1 through 5, 8, and 9 in each cycle. Receives: Drug: Venetoclax; Drug: Azacitidine |
| Pevonedistat + Venetoclax + Azacitidine | Experimental | Participants received pevonedistat 20 mg/m^2 as a 60-minute IV infusion on Days 1, 3, and 5 in each 28-day cycle. In addition participants received venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Days 3 through 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. Participants also received azacitidine 75 mg/m^2 IV or SC dosing on Days 1 through 7 or Days 1 through 5, 8, and 9 in each cycle. Receives: Drug: Pevonedistat; Drug: Venetoclax; Drug: Azacitidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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 percent (%); absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) greater than or equal to (≥) 1.0×10^9 per liter (10^9/L) (1000/microliter [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 was not observed by time of analysis, data 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.
Measured: Up to 22 months
Secondary outcomes (11)
Overall Survival (OS)
OS was defined as the time from randomization to death from any cause. Participants without documentation of death at the time of analysis were censored at the date last known to be alive. OS was analyzed using the Kaplan-Meier method.
Measured: Up to 36 months
30-Day Mortality Rate
30-day mortality rate was defined as the percentage of participants who survived at most 30 days from the first dose of study drug.
Measured: Day 30
60-Day Mortality Rate
60-day mortality rate was defined as the percentage of participants who survived at most 60 days from the first dose of study drug.
Measured: Day 60
Percentage of Participants With Complete Remission (CR)
CR rate was defined as the percentage of participants who achieved the CR as evaluated by the investigator. Assessments of disease response were based on the criteria outlined in the ELN 2017 guidelines. CR was 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).
Measured: Up to 36 months
Percentage of Participants With Composite Complete Remission (CCR)
CCR rate was defined as the percentage of participants who achieved the CR + CRi as evaluated by the investigator. Assessments of disease response were based on the criteria outlined in the ELN 2017 guidelines. CR was 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 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]).
Measured: Up to 36 months
Overall Response Rate (ORR)
ORR was defined as the percentage of participants who achieved the CR + CRi + Partial Remission (PR) as evaluated by the investigator. Assessments of disease response were based on the criteria outlined in the ELN 2017 guidelines. CR was 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 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]). PR was 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%.
Measured: Up to 36 months
Percentage of Participants With CR + CRh
CR + CRh rate was defined as the percentage of participants who achieved the CR + CRh as evaluated by the investigator. Assessments of disease response were based on the criteria outlined in the ELN 2017 guidelines. CR was 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 was 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.
Measured: Up to 36 months
Percentage of Participants With Leukemia Response
Leukemia response rate was defined as the percentage of participants who achieved the CR + CRi + PR + morphological leukemia-free state [MLFS, marrow CR (mCR)]) as evaluated by the investigator. Assessments of disease response were based on the criteria outlined in the ELN 2017 guidelines. CR was 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 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]). PR was 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.
Measured: Up to 36 months
Duration of CR and CRi
Duration of CR and CRi was defined as the time from first documentation of CR or CRi to the date of first documentation of progressive disease (PD) or relapse from CR or CRi, and was summarized descriptively using the Kaplan Meier method based on the responders. Assessments of disease response were based on the criteria outlined in the ELN 2017 guidelines. CR was 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 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]).
Measured: Up to 36 months
Time to First CR, CRi and PR
Time to first CR, CRi, and PR was defined as the time from randomization until the first documented CR, CRi or PR, whichever occurs first. Assessments of disease response were based on the criteria outlined in the ELN 2017 guidelines. CR was 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 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]). PR was 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%.
Measured: Up to 36 months
Plasma Concentration of Pevonedistat
As pre-specified in the protocol, plasma concentration-time data were planned to contribute to future pharmacokinetic (PK) population and exposure response (safety/efficacy) analyses of pevonedistat.
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Feb 2020
- Study start13 Oct 2020
- Primary completion6 Sep 2022
- Study completion6 Oct 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute Myeloid Leukemia (AML)Studies of the same condition, open and under way.
- More trials run by TakedaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 164 participants (actual)
Sponsor and investigators
- Lead sponsor
- Takeda
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Takeda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04266795
- Sponsor's protocol ID
- Pevonedistat-2002
- Other IDs
- 2019-003117-33, U1111-1239-7581, 2024-515424-36-00, 2019
- Acronym
- PEVENAZA
- Status last verified
- Aug 2026
- First submitted
- 4 Feb 2020
- Last updated
- 23 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
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.
PubMed 39606906