Clinical trial NCT04266795: A Study of Pevonedistat and Venetoclax Combined With Azacitidine to Treat Acute Myeloid Leukemia (AML) in Adults Unable to Receive Intensive Chemotherapy
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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Acute Myeloid Leukemia (AML)
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2020-02-12
Enrollment: 164
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Event-Free Survival (EFS)
timeFrame: Up to 22 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 36 months
measure: Thirty-day Mortality Rate
timeFrame: Day 30
measure: Sixty-day Mortality Rate
timeFrame: Day 60
measure: Percentage of Participants With Complete Remission (CR)
timeFrame: Up to 36 months
measure: Percentage of Participants With Composite Complete Remission (CCR)
timeFrame: Up to 36 months
measure: Overall Response Rate (ORR)
timeFrame: Up to 36 months
measure: Percentage of Participants With CR + CRh
timeFrame: Up to 36 months
measure: Percentage of Participants With Leukemia Response
timeFrame: Up to 36 months
measure: Duration of CR and CRi
timeFrame: Up to 36 months
measure: Time to First CR, CRi and PR
timeFrame: Up to 36 months
measure: Plasma Concentration of Pevonedistat
timeFrame: 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)
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center
state: California
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Orlando
country: United States
facility: AdventHealth (Florida Hospital) - Transplant Institute
state: Florida
city: Louisville
country: United States
facility: Norton Cancer Institute - Suburban
state: Kentucky
city: New Orleans
country: United States
facility: Tulane Medical Center
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Kansas City
country: United States
facility: HCA Midwest Health - SCRI - PPDS
state: Missouri
city: Lake Success
country: United States
facility: Northwell Health Cancer Institute
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Stony Brook
country: United States
facility: Stony Brook Medicine
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: The University of Oklahoma Health Sciences Center
state: Oklahoma
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Houston
country: United States
facility: Houston Methodist Cancer Center
state: Texas
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research and Treatment Center
state: Texas
city: Salt Lake City
country: United States
facility: Intermountain LDS Hospital
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University Hospital
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Tom Baker Cancer Centre
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Quebec City
country: Canada
facility: Hopital de L'enfant Jesus
state: Quebec
city: Le Mans
country: France
facility: Centre Hospitalier Le Mans
state: Sarthe
city: Bobigny
country: France
facility: Hopital Avicenne
city: Caen
country: France
facility: Institut dHematologie de Basse Normandie
city: Grenoble
country: France
facility: CHU de Grenoble
city: Lille
country: France
facility: CHRU Lille
city: Nantes
country: France
facility: CHRU Nantes
city: Nice
country: France
facility: CHU de Nice
city: Paris
country: France
facility: Hopital Saint Antoine
city: Paris
country: France
facility: Hopital Saint Louis
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Poitiers
country: France
facility: CHRU de Poitiers La Miletrie
city: Toulouse
country: France
facility: EDOG - Institut Claudius Regaud - PPDS
city: Reggio Calabria
country: Italy
facility: Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli
state: Calabria
city: Monza
country: Italy
facility: ASST di Monza - Azienda Ospedaliera San Gerardo
state: Lombardia
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Milano
city: Orbassano
country: Italy
facility: Azienda Sanitaria Ospedaliera S Luigi Gonzaga
state: Piemonte
city: Torino
country: Italy
facility: Azienda Ospedaliera Citta della Salute e della Scienza di Torino
state: Piemonte
city: Perugia
country: Italy
facility: Ospedale Santa Maria Della Misericordia Di Perugia
state: Umbria
city: Bologna
country: Italy
facility: Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo di Pavia
city: Lodz
country: Poland
facility: Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
state: Lodzkie
city: Krakow
country: Poland
facility: Szpital Uniwersytecki w Krakowie
state: Malopolskie
city: Warszawa
country: Poland
facility: MTZ Clinical Research Sp z o o
state: Mazowieckie
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii
state: Mazowieckie
city: Bialystok
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Bialymstoku
state: Podlaskie
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki Nr 2 im. Dr Jana Biziela w Bydgoszczy
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: