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

Phase 2

Active, not recruiting

Conditions: Acute Myeloid Leukemia (AML)

Interventions: Drug: Venetoclax
Drug: Pevonedistat
Drug: Azacitidine

Registration Number: NCT04266795

Lead Sponsor: Takeda

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 164

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2	Venetoclax	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 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2	Venetoclax	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.
Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2	Azacitidine	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 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2	Azacitidine	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.
Pevonedistat 20 mg/m^2 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2	Pevonedistat	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.

Primary Outcome Measures

Name	Time	Method
Event-Free Survival (EFS)	Up to 22 months	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

Name	Time	Method
Sixty-day Mortality Rate	Day 60	Mortality rate is defined as percentage of participants who survive at most 60 days from the first dose of study drug.
Overall Survival (OS)	Up to 36 months	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	Day 30	Mortality rate is defined as percentage of participants who survive at most 30 days from the first dose of study drug.
Percentage of Participants With Composite Complete Remission (CCR)	Up to 36 months	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 \[100,000/µL\]).
Percentage of Participants With Leukemia Response	Up to 36 months	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.
Percentage of Participants With Complete Remission (CR)	Up to 36 months	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 CR + CRh	Up to 36 months	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.
Plasma Concentration of Pevonedistat	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)
Overall Response Rate (ORR)	Up to 36 months	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%.
Duration of CR and CRi	Up to 36 months	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	Up to 36 months	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%.

Trial Locations

Locations (57): Houston Methodist Cancer Center
🇺🇸
Houston, Texas, United States
UC Irvine Medical Center
🇺🇸
Orange, California, United States
University Hospitals Cleveland Medical Center
🇺🇸
Cleveland, Ohio, United States
The University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Medical College of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
Stony Brook Medicine
🇺🇸
Stony Brook, New York, United States
Hopital Avicenne
🇫🇷
Bobigny, France
Ottawa Hospital
🇨🇦
Ottawa, Ontario, Canada
UC San Diego Moores Cancer Center
🇺🇸
La Jolla, California, 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
Joe Arrington Cancer Research and Treatment Center
🇺🇸
Lubbock, Texas, United States
University of Virginia Health System
🇺🇸
Charlottesville, Virginia, United States
Centre Hospitalier Lyon Sud
🇫🇷
Pierre Benite, France
CHRU de Poitiers La Miletrie
🇫🇷
Poitiers, France
Ospedale Santa Maria Della Misericordia Di Perugia
🇮🇹
Perugia, Umbria, Italy
Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi
🇮🇹
Bologna, Italy
Szpital Uniwersytecki Nr 2 im. Dr Jana Biziela w Bydgoszczy
🇵🇱
Bydgoszcz, Poland
Norton Cancer Institute - Suburban
🇺🇸
Louisville, Kentucky, United States
HCA Midwest Health - SCRI - PPDS
🇺🇸
Kansas City, Missouri, United States
University of North Carolina at Chapel Hill
🇺🇸
Chapel Hill, North Carolina, United States
Banner MD Anderson Cancer Center
🇺🇸
Gilbert, Arizona, United States
Azienda Ospedaliera Universitaria Careggi
🇮🇹
Firenze, Italy
Hopital de L'enfant Jesus
🇨🇦
Quebec City, Quebec, Canada
CHU de Grenoble
🇫🇷
Grenoble, France
MTZ Clinical Research Sp z o o
🇵🇱
Warszawa, Mazowieckie, Poland
Uniwersytecki Szpital Kliniczny w Bialymstoku
🇵🇱
Bialystok, Podlaskie, Poland
London Health Sciences Centre
🇨🇦
London, Ontario, Canada
Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli
🇮🇹
Reggio Calabria, Calabria, Italy
University of Miami Miller School of Medicine
🇺🇸
Miami, Florida, United States
AdventHealth (Florida Hospital) - Transplant Institute
🇺🇸
Orlando, Florida, United States
Tom Baker Cancer Centre
🇨🇦
Tom Baker Cancer Centre, Alberta, Canada
Centre Hospitalier Le Mans
🇫🇷
Le Mans, Sarthe, France
CHRU Nantes
🇫🇷
Nantes, France
Azienda Sanitaria Ospedaliera S Luigi Gonzaga
🇮🇹
Orbassano, Piemonte, Italy
Fondazione IRCCS Policlinico San Matteo di Pavia
🇮🇹
Pavia, Italy
University of Alberta
🇨🇦
Edmonton, Alberta, Canada
Hopital Saint Antoine
🇫🇷
Paris, France
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
ASST di Monza - Azienda Ospedaliera San Gerardo
🇮🇹
Monza, Lombardia, Italy
Istituto Clinico Humanitas
🇮🇹
Rozzano, Milano, Italy
Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie
🇵🇱
Lublin, Poland
Institut dHematologie de Basse Normandie
🇫🇷
Caen, France
CHRU Lille
🇫🇷
Lille, France
CHU de Nice
🇫🇷
Nice, France
Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
🇵🇱
Lodz, Lodzkie, Poland
Uniwersyteckie Centrum Kliniczne
🇵🇱
Gdansk, Poland
West Virginia University Hospital
🇺🇸
Morgantown, West Virginia, United States
Hopital Saint Louis
🇫🇷
Paris, France
Avera Cancer Institute
🇺🇸
Sioux Falls, South Dakota, United States
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
🇮🇹
Torino, Piemonte, Italy
Szpital Uniwersytecki w Krakowie
🇵🇱
Krakow, Malopolskie, Poland
Instytut Hematologii i Transfuzjologii
🇵🇱
Warszawa, Mazowieckie, Poland
Intermountain LDS Hospital
🇺🇸
Salt Lake City, Utah, United States
EDOG - Institut Claudius Regaud - PPDS
🇫🇷
Toulouse, France
Tulane Medical Center
🇺🇸
New Orleans, Louisiana, United States
Rhode Island Hospital
🇺🇸
Providence, Rhode Island, United States