Clinical trial NCT04778397: Study of Magrolimab in Combination With Azacitidine Versus Physician's Choice of Venetoclax in Combination With Azacitidine or Intensive Chemotherapy in Patients With TP53 Mutant Acute Myeloid Leukemia That Have Not Been Treated
Official title: A Phase 3, Randomized, Open-Label Study Evaluating the Safety and Efficacy of Magrolimab in Combination With Azacitidine Versus Physician's Choice of Venetoclax in Combination With Azacitidine or Intensive Chemotherapy in Previously Untreated Patients With TP53 Mutant Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2021-03-03
Enrollment: 258
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 goal of this clinical study is to compare the effectiveness of the study drugs, magrolimab in combination with azacitidine, versus venetoclax in combination with azacitidine in participants with previously untreated TP53 mutant acute myeloid leukemia (AML).


Eligibility criteria: Key Inclusion Criteria:

* Individuals with confirmation of acute myeloid leukemia (AML) by World Health Organization criteria, previously untreated for AML, and who have presence of at least 1 TP53 gene mutation that is not benign or likely benign based on evaluation by either central laboratory or an approved local laboratory (after central review of the bone marrow TP53 mitigation next-generation sequencing test results) (individuals with biallelic 17p deletions, loss of both 17p alleles, are eligible based on locally evaluated cytogenetics/karyotype/fluorescence in situ hybridization (FISH) report).
* Individuals with white blood cell (WBC) count ≤ 20×10\^3/microliter (μL) prior to randomization. If the individual's WBC is \> 20×10\^3/μL prior to randomization, the individual can be enrolled, assuming all other eligibility criteria are met. However, the WBC should be ≤ 20×10\^3/μL prior to the first dose of study treatment and prior to each magrolimab dose the first 4 weeks (if the individual is randomized to the experimental arm) Note: Individuals can be treated with hydroxyurea and/or leukapheresis throughout the study or prior to randomization to reduce the WBC to ≤ 20×10\^3/μL to enable eligibility for study drug dosing.
* The hemoglobin must be ≥ 9 grams per deciliter (g/dL) prior to initial dose of study treatment.

Notes: Transfusions are allowed to meet hemoglobin eligibility.

* Individual has provided informed consent.
* Individual is willing and able to comply with clinic visits and procedure outlined in the study protocol.
* Individuals must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, except for individuals less than 75 years of age and appropriate for non-intensive treatment. For these individuals, the ECOG performance status score may be 0 to 3.
* Individuals must have adequate renal function as demonstrated by a creatinine clearance ≥ 30 milliliters per minute calculated by the Cockcroft Gault formula.
* Adequate cardiac function as demonstrated by:

  * Lack of symptomatic congestive heart failure and clinically significant cardiac arrhythmias and ischemic heart disease.
  * Left ventricular ejection fraction (LVEF) \> 50% for individuals appropriate for intensive therapy.
* Adequate liver function as demonstrated by:

  * Aspartate aminotransferase ≤ 3.0 × upper limit of normal (ULN).
  * Alanine aminotransferase ≤ 3.0 × ULN.
  * Total bilirubin ≤ 1.5 × ULN, or primary unconjugated bilirubin ≤ 3.0 × ULN if individual has a documented history of Gilbert's syndrome or genetic equivalent.
* Pretreatment blood cross-match completed.
* Males and females of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception.
* Individuals must be willing to consent to mandatory pretreatment and on-treatment bone marrow biopsies (aspirate and trephines).

Key Exclusion Criteria:

* Positive serum pregnancy test.
* Breastfeeding female.
* Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient.
* Prior treatment with any of the following:

  * Cluster of differentiation 47 (CD47) or signal regulatory protein alpha (SIRPα)-targeting agents
  * Antileukemic therapy for the treatment of AML (excluding hydroxyurea), hypomethylating agent (HMA), low dose cytarabine and/or venetoclax.

Note: Individuals with prior myelodysplastic syndrome (MDS) who have not received prior HMAs or chemotherapeutic agents for MDS are allowed on study. Other prior MDS therapies including, but not limited to, lenalidomide, erythroid stimulating agents, or similar red blood cell (RBC)-direct therapies, were allowed. Localized non-central nervous system (CNS) radiotherapy, erythroid and/or myeloid growth factors, hormonal therapy with luteinizing hormone-releasing hormone agonists for prostate cancer, hormonal therapy or maintenance for breast cancer, and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand inhibitors are also not criteria for exclusion.

* Individuals who are appropriate for intensive treatment but who have been previously treated with maximum cumulative doses of idarubicin and/or other anthracyclines and anthracenediones will be excluded.
* Individuals receiving any live vaccine within 4 weeks prior to initiation of study treatments.
* For individuals appropriate for intensive therapy, individuals treated with trastuzumab within 7 months prior to initiation of study treatments.
* Current participation in another interventional clinical study.
* Known inherited or acquired bleeding disorders.
* Individuals appropriate for non-intensive therapy, who have received treatment with strong and/or moderate cytochrome P450 enzyme 3A (CYP3A) inducers within 7 days prior to the initiation of study treatments.
* Individuals appropriate for non-intensive therapy who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days prior to the initiation of study treatment.
* Individuals appropriate for non-intensive therapy who have malabsorption syndrome or other conditions that preclude enteral route of administration.
* Clinical suspicion of active CNS involvement with AML.
* Individuals who have acute promyelocytic leukemia.
* Significant disease or medical conditions, as assessed by the investigator and sponsor, that would substantially increase the risk-benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III-IV.
* Second malignancy, except MDS, treated basal cell or localized squamous skin carcinomas, localized prostate cancer, or other malignancies for which individuals are not on active anti-cancer therapies and have had no evidence of active malignancy for at least ≥ 1 year Note: Individuals on maintenance therapy alone who have no evidence of active malignancy for at least ≥ 1 year are eligible.
* Known active or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or human immunodeficiency virus (HIV) infection in medical history.
* Active HBV, and/or active HCV, and/or HIV following testing at screening:

  * Individuals who test positive for hepatitis B surface antigen (HBsAg). Individuals who test positive for hepatitis B core antibody (anti-HBc) will require HBV deoxyribose nucleic acid (DNA) by quantitative polymerase chain reaction (PCR) for confirmation of active disease.
  * Individuals who test positive for HCV antibody. These individuals will require HCV ribose nucleic acid (RNA) quantitative PCR for confirmation of active disease.
  * Individuals who test positive for HIV antibody.
  * Individuals not currently receiving antiviral therapy and who have an undetectable viral load in the prior 3 months may be eligible for the study.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Overall Survival (OS) in Participants Appropriate for Non-intensive Therapy
timeFrame: Up to 2.1 years
Secondary outcomes:
measure: Overall Survival in All Participants
timeFrame: Up to 2.1 years
measure: Event-Free Survival (EFS) in All Participants
timeFrame: Up to 2.1 years
measure: Rate of Complete Remission (CR) in All Participants
timeFrame: Up to 2.1 years
measure: Rate of CR Without Minimal Residual Disease (CR MRD-) in All Participants
timeFrame: Up to 2.1 years
measure: Rate of CR and CR With Partial Hematologic Recovery (CR+CRh) in All Participants
timeFrame: Up to 2.1 years
measure: Duration of CR (DCR)
timeFrame: Up to 2.1 years
measure: Duration of CR+CRh
timeFrame: Up to 2.1 years
measure: Percentage of Participants Experiencing Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs)
timeFrame: First dose date up to 1.3 years plus 70 days
measure: Percentage of Participants Experiencing Grade 3 or 4 Treatment-Emergent Laboratory Abnormalities
timeFrame: First dose date up to 1.3 years plus 70 days
measure: Serum Concentration of Magrolimab
timeFrame: Predose on Days 1, 4, 8, 11; Days 29 and 57 Predose and 1 hour Postdose; Predose on Days 113, 169, 253, 281 and 337
measure: Percentage of Participants With Anti-Magrolimab Antibodies
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Duarte
country: United States
facility: City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
state: California
city: Los Angeles
country: United States
facility: USC/ Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Orange
country: United States
facility: UC Irvine Health
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Pembroke Pines
country: United States
facility: Memorial Cancer Institute
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital/Main Lab
state: Illinois
city: Chicago
country: United States
facility: The University of Chicago Medical Centre
state: Illinois
city: Fairway
country: United States
facility: University of Kansas Hospital
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: New Orleans
country: United States
facility: Tulane Medical center
state: Louisiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center Outpatient Pharmacy
state: Minnesota
city: Kansas City
country: United States
facility: MidAmerica Division, Inc., c/o Research Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: SSM Health Saint Louis University Hospital
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center - Herbert Irving Pavilion
state: New York
city: Chapel Hill
country: United States
facility: UNC Hospitals, The University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke Blood Cancer Center
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center/ James Cancer Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center - OU Health Stephenson Cancer Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Thomas Jefferson University, Sidney Kimmel Cancer Center, Clinical Research Organization
state: Pennsylvania
city: Greenville
country: United States
facility: St. Francis Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute
state: South Carolina
city: Houston
country: United States
facility: Baylor College of Medicine Medical Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute ,The University of Utah
state: Utah
city: Milwaukee
country: United States
facility: Froedtert Hospital / Medical College of Wisconsin
state: Wisconsin
city: Garran
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Waratah
country: Australia
facility: Calvary Master Newcastle
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital / Department of Haematology and Bone Marrow Transplantation
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Geelong
country: Australia
facility: Andrew Love Cancer Centre, University Hospital Geelong
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred
state: Victoria
city: Melbourne
country: Australia
facility: St Vincents Hospital Melbourne
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Linz
country: Austria
facility: Univ. -Klinik für Hämatologie und Internistische Onkologie, Kepler Universitätskilkun GmbHMed
city: Salzburg
country: Austria
facility: Uniklinikum Salzburg, Universitatsklinik f. Innere Medizin III der PMU
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan Brugge-Oostende AV
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Charleroi
country: Belgium
facility: Grand Hôpital De Charleroi - Notre Dame
city: Edegem
country: Belgium
facility: Universitaire Ziekenhuis Antwerpen
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Roeselare
country: Belgium
facility: AZ Delta vzw
city: Calgary
country: Canada
facility: Tom Baker Cancer Center
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
city: Montreal
country: Canada
facility: CIUSSS de L'Est-de-L'Ile-de- Montreal - Hopital Maisonneuve-Rosemont
city: Montreal
country: Canada
facility: McGill University Health Centre
city: Toronto
country: Canada
facility: Sunnybrook Research Institute
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Odense C
country: Denmark
facility: Odense University Hospital
city: Angers cedex
country: France
facility: CHU d'Angers
city: Caen cedex
country: France
facility: CHU de Caen
city: Lille
country: France
facility: CHRU Lille - Hospital Claude Huriez
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: Central Hospital Lyon Sud
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Nantes
country: France
facility: CHU de Nantes, Hotel Dieu
city: Nice
country: France
facility: CHU Nice - Hopital Archet 1
city: Paris
country: France
facility: Gustave Roussy
city: Pessac
country: France
facility: Hopital Haut-Leveque
city: Toulouse
country: France
facility: IUCT Oncopole
city: Vandoeuvre-lès-Nancy
country: France
facility: Hopitaux de Brabois
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen, Medizinische Klunuk IV - Klinik fur Hamatologie, Onkologie, Hamastaseologie und Srammzelltransplantation
city: Berlin
country: Germany
facility: Dept. of Hematology, Oncology and Tumor Immunology, Charite- University Medicine Berlin, Campus Virchow Klinikum
city: Braunschweig
country: Germany
facility: Department of Hematology and Oncology, Braunschweig Community Hospital
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus Dresden an der Technische Universitat Dresden, Medizinische Klinik und Poliklinik 1, Bereich Hamatologie
city: Dusseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf -Klinik für Hämatologie, Onkologie und Klinische Immunologie
city: Hamburg
country: Germany
facility: Dept. of Medicine II, University Hospital Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg, Innere Medizin V, Hamatologie, Onkologie und Rheumatologie
city: Kiel
country: Germany
facility: Universitatsklinikum Schleswig-Holstein
city: Köln
country: Germany
facility: Universitatsklinikum Koln
city: Ludwigshafen
country: Germany
facility: Klinikum Ludwigshafen Medizinische Klinik A
city: Muenchen
country: Germany
facility: Klinikum rechts der Isar der Technischen Universitat Munchen, Klinik und Poliklinik fur Innere Medizin III
city: München
country: Germany
facility: LMU - Klinikum der Universitat Munchen, Medizinische Klinik und Poliklinik III, Campus Grosshadern
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm, Zentrum fur Innere Medizin, Innere Medizin III
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital, The Chinese University of Hong Kong
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria delle Marche
city: Bari
country: Italy
facility: AOU Consorziale Policlinico Bari
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola-Malphigi U.O Ematologia
city: Meldola
country: Italy
facility: Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRS - Oncologia Medica
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale Antonio Cardarelli U.O.S.C. di Ematologia con Trapianto di Midollo Osseo
city: Perugia
country: Italy
facility: SC Ematologia, Azienda Ospedaliera di Perugia - Santa Maria della Misericordia
city: Pesaro
country: Italy
facility: AORM - AO Riuniti Marche Norde - Pesaro Presidio "San Salvatore" - Muraglia
city: Roma
country: Italy
facility: Fondazione PTV Policinico Tor Vergata
city: Torino
country: Italy
facility: SCDU Ematologia e Terrapie cellulari AO O Ordine Mauriziano Torino
city: Varese
country: Italy
facility: ASST Sette Laghi - Ospedale di Circolo e Fondazione Macchi
city: Amagasaki
country: Japan
facility: Hyogo Prefectural Amagasaki General Medical Center
city: Chiba
country: Japan
facility: Chiba Aoba Municipal Hospital
city: Chuo-City
country: Japan
facility: University of Yamanashi Hospital
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Fukushima-Shi
country: Japan
facility: Fukushima Medical University Hospital
city: Hokkaido
country: Japan
facility: Aiiku Hospital
city: Isehara
country: Japan
facility: Tokai University School of Medicine
city: Kanazawa
country: Japan
facility: Kanazawa University Hospital
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
city: Kitakyushu-shi
country: Japan
facility: Hospital of the University of Occupational and Environmental Health, Japan
city: Kobe-city
country: Japan
facility: Kobe City Medical Center General Hospital
city: Maebashi
country: Japan
facility: Gunmaken Saiseikai Maebashi Hospital
city: Matsuyama
country: Japan
facility: Ehime Prefectural Center Hospital
city: Nagasaki
country: Japan
facility: Nagasaki University Hospital
city: Nagoya-Shi
country: Japan
facility: Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital
city: Nagoya
country: Japan
facility: Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital
city: Okayama-Shi
country: Japan
facility: Okayama University Hospital
city: Osaka-Shi
country: Japan
facility: Osaka Metropolitan University Hospital
city: Osakasayama
country: Japan
facility: Kindai University Hospital
city: Sendai
country: Japan
facility: National University Corporation Tohoku University Tohoku University Hospital
city: Shinagawa-Ku
country: Japan
facility: NTT Medical Center Tokyo
city: Yamagata
country: Japan
facility: Yamagata University Hospital
city: Yoshida-gun
country: Japan
facility: University of Fukui Hospital
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Barcelona
country: Spain
facility: Hospital del la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia
city: Burgos
country: Spain
facility: Complejo Asistencial Universitario de Burgos/H.U. de Burgos
city: Cordoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Cáceres
country: Spain
facility: Complejo Hospitalario San Pedro de Alcantara
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Doctor Negrin
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: MD Anderson Cancer Center Madrid
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra - Pamplona (Main Site)
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca - Hsopital Clinico
city: Santander
country: Spain
facility: Hospital U. Marques de Valdecilla
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari I Politècnic La Fe
city: Lund
country: Sweden
facility: Universitetssjukhus, Hematologimottagnungen
city: Basel
country: Switzerland
facility: Universitatsspital Basel - Klinik fur Hamatrologie, Bereich Innere Medizin
city: Berne
country: Switzerland
facility: Inselspital, Universitatsspital Bern - Universitatsklinik fur Medizinisch Onkologie
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: Boston
country: United Kingdom
facility: United Lincolnshire Hospitals NHS Trust, Pilgrim Hospital, Sibsey Road
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospital NHS Foundation Trust
city: Cardiff Wales
country: United Kingdom
facility: Cardiff and Vale University Health Board
city: City of London
country: United Kingdom
facility: Barts Health NHS Trust
city: Dundee
country: United Kingdom
facility: NHS Tayside
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: King's College NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospital NHS Foundation Trust
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: Withington
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References: