Study of Magrolimab Combinations in Participants With Myeloid Malignancies
NCT ID: NCT04778410
Last Updated: 2025-03-20
Study Results
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View full resultsBasic Information
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TERMINATED
PHASE2
54 participants
INTERVENTIONAL
2021-06-28
2024-03-04
Brief Summary
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Detailed Description
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* Venetoclax (Ven)
* Azacitidine (Aza)
* Mitoxantrone, etoposide, and cytarabine (MEC)
This study consists of 3 safety run-in cohorts;
* Safety Run-in Cohort 1 (1L Unfit AML Mag + Ven + Aza)
* Safety Run-in Cohort 2 (R/R AML Mag + MEC)
* Safety Run-in Cohort 3 (Post-chemo Maintenance Mag + CC-486)
Participants will receive treatment at the assigned dose level for at least 4 cycles in the Safety Run-in cohorts, after which they may continue at the assigned dose level or switch to the RP2D upon agreement between the investigator and the sponsor. After completion of each safety run-in cohort and identification of the RP2D for that cohort, participants may be enrolled into the corresponding Phase 2 cohorts;
* Phase 2 Cohort 1 (1L Unfit AML Mag + Ven + Aza)
* Phase 2 Cohort 2 (R/R AML Mag + MEC)
* Phase 2 Cohort 3 (Post-chemo Maintenance Mag + CC-486)
Cycle length is 28 days for both the Safety Run-in and Phase 2 cohorts.
Note: All cohorts are closed to screening and enrollment.
Conditions
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Study Design
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NON_RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
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Cohort 1 (1L Unfit AML): Magrolimab + Venetoclax + Azacitidine
Participants with newly diagnosed untreated acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy will receive magrolimab 1 mg/kg on Days 1, 4; 15 mg/kg on Day 8; 30 mg/kg on Days 11, 15, and then every week (QW) x 5 doses; 30 mg/kg every 2 weeks (Q2W) beginning 1 week after the 5 weekly 30 mg/kg dose in every 28-day cycle along with azacitidine and venetoclax first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
Magrolimab
Administered intravenously
Azacitidine
Administered either subcutaneously or IV, 75 mg/milligram per square (m\^2) on Days 1 to 7 or Days 1 to 5, 8 and 9 during every cycle
Venetoclax
Administered orally at a dose of 100 mg on Day 1, 200 mg on Day 2, 400 mg on Days 3-28 during Cycle 1, followed by 400 mg on Days 1-28 during every cycle
Cohort 2 (R/R AML): Magrolimab + Mitoxantrone + Etoposide + Cytarabine
Participants with relapsed/refractory (RR) AML after intensive induction chemotherapy will receive magrolimab 1 mg/ on Days 1, 4; 15 mg/kg, on Day 8; 30 mg/kg on Days 11, 15, and then QW x 5 doses; 30 mg/kg Q2W beginning 1 week after the 5 weekly 30 mg/kg dose along with mitoxantrone + etoposide + cytarabine (MEC) first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
Magrolimab
Administered intravenously
Mitoxantrone
Administered intravenously, 8 mg/m\^2 on Days 1-5 during Cycle 1 to Cycle 3
Etoposide
Administered intravenously, 100 mg/m\^2 on Days 1-5 during Cycle 1 to Cycle 3
Cytarabine
Administered intravenously, 1000 mg/m\^2 on Days 1-5 during Cycle 1 to Cycle 3
Cohort 3 (Post-Chemo Maintenance): Magrolimab + CC-486
Participants with AML who achieved CR or CRi with MRD positivity following intensive induction chemotherapy will receive magrolimab 1 mg/kg on Days 1, 4; 15 mg/kg on Day 8; 30 mg/kg on Days 11, 15, and then QW x 5 doses; 30 mg/kg Q2W beginning 1 week after the 5 weekly 30 mg/kg dose along with CC-486 as maintenance therapy first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
Magrolimab
Administered intravenously
CC-486
Administered orally, 300 mg on Days 1-14 during each cycle
Interventions
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Magrolimab
Administered intravenously
Azacitidine
Administered either subcutaneously or IV, 75 mg/milligram per square (m\^2) on Days 1 to 7 or Days 1 to 5, 8 and 9 during every cycle
Venetoclax
Administered orally at a dose of 100 mg on Day 1, 200 mg on Day 2, 400 mg on Days 3-28 during Cycle 1, followed by 400 mg on Days 1-28 during every cycle
Mitoxantrone
Administered intravenously, 8 mg/m\^2 on Days 1-5 during Cycle 1 to Cycle 3
Etoposide
Administered intravenously, 100 mg/m\^2 on Days 1-5 during Cycle 1 to Cycle 3
Cytarabine
Administered intravenously, 1000 mg/m\^2 on Days 1-5 during Cycle 1 to Cycle 3
CC-486
Administered orally, 300 mg on Days 1-14 during each cycle
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* White blood cell (WBC) count ≤ 20 × 10\^3/microliter (μL) prior to first dose of study treatment. If the individual's WBC count is \> 20 × 10\^3/ μL prior to first dose of study treatment, the individual can be enrolled, assuming all other eligibility criteria are met
* For individuals with prior cardiac history, the hemoglobin must be ≥ 9 grams per deciliter (g/dL) prior to initial dose of study treatment. Transfusions are allowed to meet hemoglobin eligibility
* Adequate liver function
* Adequate renal function
* Individual has provided informed consent
* Individual is willing and able to comply with clinic visits and procedures outlined in the study protocol
* 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 (trephines), unless not feasible as determined by the investigator and discussed with the sponsor
Safety Run-in Cohort 1 and Phase 2 Cohort 1 (Ineligible (1L) Unfit acute myeloid leukemia (AML) Magrolimab + Venetoclax + Azacitidine):
* Newly diagnosed, previously untreated individuals with histological confirmation of AML by world health organization (WHO) criteria who are ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age, comorbidity, or other factors. Individuals must be considered ineligible for induction therapy defined by the following:
* ≥ 75 years of age
* ≥ 18 to 74 years of age with at least 1 of the following comorbidities:
* Diffusing capacity of the lung of carbon monoxide ≤ 65% or forced expiratory volume in 1 second ≤ 65%
* Left ventricular ejection fraction (LVEF) ≤ 50%
* Creatinine clearance (CrCl) \< 45 mL/min calculated by the Cockcroft-Gault formula or measured by 24 hours' urine collection
* Any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy that must be approved by the sponsor medical monitor before study enrollment
* Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3
* Individuals who have not received prior anti-leukemia therapy for AML (excluding hydroxyurea or oral etoposide), hypomethylating agent (HMA), low-dose cytarabine, and/or venetoclax. Individuals with prior myelodysplastic syndrome (MDS) cannot have received a prior HMA, venetoclax, or a chemotherapeutic agent. Other prior MDS therapies, including but not limited to lenalidomide, erythroid-stimulating agents, or similar red blood cell (RBC) -direct therapies, are allowed
* Individuals who have not received strong and/or moderate cytochrome P450 enzyme (CYP) 3A inducers (such as St. John's Wort) within 7 days prior to the initiation of study treatment
* Individuals who have not consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days prior to the initiation of study treatment or are willing to discontinue consumption of these while receiving study drug
* Individuals without malabsorption syndrome or other conditions that preclude enteral route of administration
Safety Run-in Cohort 2 and Phase 2 Cohort 2 (Relapsed/refractory (R/R) AML Magrolimab+Mitoxantrone + Etoposide + Cytarabine (MEC)):
* Individuals with confirmation of AML by WHO criteria who are refractory to or have experienced first relapse after initial intensive chemotherapy. Note: Individuals who are relapsed after or are refractory to more than 1 line of anti-AML treatment are not eligible. Individuals who relapsed after undergoing stem cell transplant may be eligible.
* At least 2 weeks must have elapsed since any prior anti-leukemia agents. Note: Localized non-central nervous system (CNS) radiotherapy, hydroxyurea, and erythroid and/or myeloid growth factors are not criteria for exclusion
* ECOG performance status of 0 to 2
* Individuals with LVEF \> 50%, lack of symptomatic congestive heart failure, or clinically significant cardiac arrhythmias
* Must not have been treated with trastuzumab within 7 months prior to the initiation of study treatment
* Individuals who have not previously received maximum cumulative doses of anthracyclines and anthracenediones
* Individuals without degenerative or toxic encephalopathies.
* Individuals who did not undergo hematopoietic SCT in the past 100 days, are not on immunosuppressive therapy post SCT in the 2 weeks prior to the first dose of study treatment, or have no active clinically significant graft-versus-host disease.
Safety Run-in Cohort 3 and Phase 2 Cohort 3 (Post-chemo Maintenance Magrolimab+CC-486):
* Individuals with histological confirmation of AML by WHO criteria who achieved a complete remission (CR) or CR with incomplete hematologic recovery (CRi) with presence of MRD (MRD positive by flow cytometry assay, defined as ≥ 0.1% detectable MRD) after intensive induction chemotherapy with or without consolidation therapy, prior to starting maintenance therapy for newly diagnosed AML, and who are not candidates for hematopoietic stem cell transplantation (SCT) within 1 year of achievement of initial remission
* ECOG performance status of 0 to 2
* Individuals without malabsorption syndrome or other conditions that preclude enteral route of administration
Exclusion Criteria
* Breastfeeding female
* Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient
* Individuals receiving any live virus vaccine within 4 weeks prior to initiation of study treatments
* Prior treatment with cluster of differentiation 47 (CD47) or signal regulatory protein alpha (SIRPα) -targeting agents
* Current participation in another interventional clinical trial
* Known inherited or acquired bleeding disorders
* Clinical suspicion of or documented 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 over 1 year. Previous hormonal therapy with luteinizing hormone-releasing hormone (LHRH) agonists for prostate cancer and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors are not criteria for exclusion
* 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 or C infection or human immunodeficiency virus
18 Years
ALL
No
Sponsors
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Gilead Sciences
INDUSTRY
Responsible Party
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Principal Investigators
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Gilead Study Director
Role: STUDY_DIRECTOR
Gilead Sciences
Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
Duarte, California, United States
USC/Norris Comprehensive Cancer Center
Los Angeles, California, United States
Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
Los Angeles, California, United States
Stanford Cancer Center
Palo Alto, California, United States
Sylvester Comprehensive Cancer Center
Miami, Florida, United States
The University of Chicago Medical Center
Chicago, Illinois, United States
Karmanos Cancer Institute
Detroit, Michigan, United States
Washington University School of Medicine
St Louis, Missouri, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Levine Cancer Institute
Charlotte, North Carolina, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
OU Health, Stephenson Cancer Center
Oklahoma City, Oklahoma, United States
Baylor University Medical Center
Dallas, Texas, United States
MD Anderson Cancer Center
Houston, Texas, United States
Swedish Cancer Institute
Seattle, Washington, United States
Froedtert Hospital & the Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Austin Health
Heidelberg, Victoria, Australia
The Alfred Hospital
Melbourne, Victoria, Australia
Royal Perth Hospital
Perth, Western Australia, Australia
Oxford University Hospitals NHS Foundation Trust, Churchill Hospital
Oxford, , United Kingdom
Countries
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References
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Mannis GN, Abboud C, Daver NG, Guru Murthy GS, Wang ES, Bradley TJ, et al. Tolerability and Efficacy of Magrolimab Plus Mitoxantrone, Etoposide, and Cytarabine (MEC) in Patients with Acute Myeloid Leukemia (AML) Refractory/Relapsed (R/R) After Induction Chemotherapy (IC). European Hematology Association (EHA) 13-16 June 2024.
Mannis GN, Abboud CN, Daver NG, Murthy GSG, Wang ES, Bradley TJ, Yaghmour G, Vachhani P, Balasubramanian SK, Chua CC, Fong CY, Asch AS, Dong M, Li S, Bagheri T, Doshi P, Vyas P, Malki MMA. Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients With Acute Myeloid Leukaemia. EJHaem. 2025 May 13;6(3):e70051. doi: 10.1002/jha2.70051. eCollection 2025 Jun.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Related Links
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Gilead Clinical Trials Website
Other Identifiers
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2021-003833-13
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
GS-US-546-5920
Identifier Type: -
Identifier Source: org_study_id
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