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Study of Magrolimab Combinations in Participants With Myeloid Malignancies

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ClinicalTrials.gov Identifier: NCT04778410
Recruitment Status : Recruiting
First Posted : March 3, 2021
Last Update Posted : November 23, 2021
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Tracking Information
First Submitted Date  ICMJE February 22, 2021
First Posted Date  ICMJE March 3, 2021
Last Update Posted Date November 23, 2021
Actual Study Start Date  ICMJE June 28, 2021
Estimated Primary Completion Date June 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 18, 2021)
  • Rate of Complete Remission (CR) (Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The CR rate is the percentage of participants who achieve CR [Complete remission without minimal residual disease (CRMRD-) or complete remission with positive or unknown minimal residual disease (CRMRD+/unk)] as determined by the investigator based on prespecified criteria while on study prior to initiation of any new anti-cancer therapy. Assessment of leukemia response in participants with acute myeloid leukemia (AML) will be conducted based on the European Leukemia Net (ELN) recommendations for AML.
  • Minimal Residual Disease Negative Complete Remission Rate (Phase 2 Cohort 3) [ Time Frame: First dose date up to 5 years ]
    The minimal residual disease (MRD) negative CR rate is defined as the percentage of participants who maintain CRas determined by the investigator based on prespecified criteria and reach MRD negative disease status as determined using multiparameter flow cytometry with a sensitivity of < 0.1% while on study prior to initiation of any new anti-AML therapy. Assessment of leukemia response in participants with AML will be conducted based on the ELN recommendations for AML.
  • Percentage of Participants Experiencing Dose-limiting Toxicities (DLTs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (Safety Run-in Cohorts 1, 2, and 3) [ Time Frame: First dose date up to 28 days of the first dosing cycle ]
    A DLT is defined as any Grade 4 or higher hematologic toxicity or Grade 3 or higher nonhematologic toxicity that has worsened in severity from pretreatment baseline during the 4-week DLT assessment period and is related to magrolimab or magrolimab combination. Cycle length is 28 days.
  • Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAE's) According to the NCI CTCAE Version 5.0 (Safety Run-in Cohorts 1, 2, and 3) [ Time Frame: Safety Run-in Cohorts 1 and 3: First dose date up to 24 months plus 70 days; Safety Run-in Cohort 2: First dose date up to 12 months plus 70 days ]
    A treatment-emergent adverse event (TEAE) will be defined as any AE that begins on or after the date of first dose of study drug up to the date of last dose of study drug plus 70 days.
  • Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities According to the NCI CTCAE Version 5.0 (Safety Run-in Cohorts 1, 2, and 3) [ Time Frame: Safety Run-in Cohorts 1 and 3: First dose date up to 24 months plus 70 days; Safety Run-in Cohort 2: First dose date up to 12 months plus 70 days ]
    Treatment-emergent laboratory abnormalities will be defined as values that increase at least 1 toxicity grade from baseline at any time point postbaseline and will be summarized by treatment group. If baseline data are missing, then any graded abnormality (ie, at least Grade 1) will be considered treatment emergent.
Original Primary Outcome Measures  ICMJE
 (submitted: March 1, 2021)
  • Rate of Complete Remission (CR) or Complete Remission with Incomplete Hematologic Recovery (CRi) (CR/CRi) (Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The CR/CRi rate is the percentage of participants who achieve CR [Complete remission without minimal residual disease (CRMRD-) or complete remission with positive or unknown minimal residual disease (CRMRD+/unk)] or CRi as determined by the investigator based on prespecified criteria while on study prior to initiation of any new anti-cancer therapy. Assessment of leukemia response inpatients with acute myeloid leukemia (AML) will be conducted based on the European Leukemia Net (ELN) recommendations for AML.
  • Minimal Residual Disease Negative Response Rate (Phase 2 Cohort 3) [ Time Frame: First dose date up to 5 years ]
    The minimal residual disease (MRD) negative response rate is defined as the percentage of participants who maintain CR/CRi as determined by the investigator based on prespecified criteria and reach MRD negative disease status as determined using multiparameter flow cytometry with a sensitivity of < 0.1% while on study prior to initiation of any new anti-cancer therapy. Assessment of leukemia response in patients with AML will be conducted based on the ELN recommendations for AML.
  • Percentage of Participants Experiencing Dose-limiting Toxicities (DLTs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (Safety Run-in Cohorts 1, 2, and 3) [ Time Frame: First dose date up to 28 days of the first dosing cycle ]
    A DLT is defined as any Grade 4 or higher hematologic toxicity or Grade 3 or higher nonhematologic toxicity that has worsened in severity from pretreatment baseline during the 4-week DLT assessment period and is related to magrolimab or magrolimab combination. Cycle length is 28 days.
  • Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAE's) According to the NCI CTCAE Version 5.0 (Safety Run-in Cohorts 1, 2, and 3) [ Time Frame: Safety Run-in Cohorts 1 and 3: First dose date up to 24 months plus 30 days; Safety Run-in Cohort 2: First dose date up to 12 months plus 30 days ]
    A treatment-emergent adverse event (TEAE) will be defined as any AE that begins on or after the date of first dose of study drug up to the date of last dose of study drug plus 30 days.
  • Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities According to the NCI CTCAE Version 5.0 (Safety Run-in Cohorts 1, 2, and 3) [ Time Frame: Safety Run-in Cohorts 1 and 3: First dose date up to 24 months plus 30 days; Safety Run-in Cohort 2: First dose date up to 12 months plus 30 days ]
    Treatment-emergent laboratory abnormalities will be defined as values that increase at least 1 toxicity grade from baseline at any time point postbaseline and will be summarized by treatment group. If baseline data are missing, then any graded abnormality (ie, at least Grade 1) will be considered treatment emergent.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2021)
  • Overall Response Rate (ORR) including Complete Remission/Complete Remission with Incomplete Hematologic Recovery (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The complete remission (CR)/Complete Remission with Incomplete Hematologic Recovery (CRi) rate is the percentage of participants who achieve CR (CRMRD- or CRMRD+/unk) or CRi as determined by the investigator based on prespecified criteria while on study prior to initiation of any new anti-AML therapy. Assessment of leukemia response in participants with AML will be conducted based on the ELN recommendations for AML.
  • Complete Remission or Complete Remission with Partial Hematologic Recovery Rate (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The complete remission or complete remission with partial hematologic recovery (CR/CRh) rate is the percentage of participants who achieve CR (CRMRD- or CRMRD+/unk) or CRh as determined by the investigator based on prespecified criteria while on study prior to initiation of any new anti-cancer therapy. Assessment of leukemia response in participants with AML will be conducted based on the ELN recommendations for AML.
  • Duration of Response (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The duration of response (DOR) is measured from the time assessment criteria that are met for CR (CRMRD- or CRMRD+/unk), CRi, CRh, PR, or MLFS, whichever is first recorded, until the first date of AML relapse, progressive disease, or death.
  • Duration of Complete Remission (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The duration of CR is measured from the time the assessment criteria are first met for CR (CRMRD- or CRMRD+/unk) until the first date of AML relapse or death.
  • Duration of Complete Remission or Complete Remission with Incomplete Hematologic Recovery (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The duration of CR/CRi is measured from the time the assessment criteria are first met for CR (CRMRD- or CRMRD+/unk) or CRi until the first date of AML relapse or death.
  • Duration of Complete Remission or Complete Remission with Partial Hematologic Recovery (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The duration of CR/CRh is measured from the time the assessment criteria are first met for CR (CRMRD- or CRMRD+/unk) or CRh until the first date of AML relapse or death.
  • Event-Free Survival (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    Event-free survival (EFS) is defined as the time from the date of the first dose of study treatment to the earliest date of documented relapse from CR/CRi, treatment failure (defined as failure to achieve CR/CRi before the fifth cycle of magrolimab+venetoclax+azacitidine in Phase 2 Cohort 1 and before the third cycle of magrolimab + MEC in Phase 2 Cohort 2), or death from any cause. Cycle length is 28 days.
  • Relapse-Free Survival (Safety Run-in Cohort 3; Phase 2 Cohort 3) [ Time Frame: First dose date up to 5 years ]
    Relapse-free survival (RFS) is measured from the time of the first dose of study treatment until the first date of AML relapse or death from any cause, whichever comes first.
  • Minimal Residual Disease Negative Complete Remission or Complete Remission with Incomplete Hematologic Recovery (Safety Run-in Cohort 3; Phase 2 Cohort 3) [ Time Frame: First dose date up to 5 years ]
    The MRD negative CR/CRi rate is defined as the proportion of participants who maintain CR/CRi as determined by the investigator and reach MRD negative disease status on 2 consecutive bone marrow assessments as determined using multiparameter flow cytometry with a sensitivity of < 0.1% while on study prior to initiation of any new anti-AML therapy.
  • Duration of Minimal Residual Disease Negative Complete Remission (Safety Run-in Cohort 3; Phase 2 Cohort 3) [ Time Frame: First dose date up to 5 years ]
    The duration of MRD negative CR is measured from the time the participant achieves MRD-negative status and maintains CR until the first date of AML relapse, loss of MRD negative status, or death.
  • Duration of Minimal Residual Disease Negative Complete Remission or Complete Remission with Incomplete Hematologic Recovery (Safety Run-in Cohort 3; Phase 2 Cohort 3) [ Time Frame: First dose date up to 5 years ]
    The duration of MRD negative CR/CRi is measured from the time the participant achieves MRD-negative status and maintains CR/CRi until the first date of AML relapse, loss of MRD negative status, or death.
  • Overall Survival (OS) (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Safety Run-in Cohorts 1 and 2: First dose date up to 3 years; Safety Run-in Cohort 3: First dose date up to 5 years; Phase 2 Cohorts 1 and 2: First dose date up to 3 years; Phase 2 Cohort 3: First dose date up to 5 years ]
    The overall survival (OS) is measured from the date of the first dose of study treatment to the date of death from any cause.
  • Red Blood Cell Transfusion Independence Rate (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Safety Run-in Cohorts 1 and 3: First dose date up to 24 months; Safety Run-in Cohort 2: First dose date up to 12 months; Phase 2 Cohorts 1 and 3: First dose date up to 24 months; Phase 2 Cohort 2: First dose date up to 12 months ]
    The red blood cell (RBC) transfusion independence rate is the percentage of participants who have a 56-day or longer period with no RBC or whole blood transfusion at any time between the date of the first dose and discontinuation of study treatment among all participants who are RBC transfusion-dependent at baseline, defined as having received an RBC or whole blood transfusion within the 28days prior to the first dose of study treatment (conversion rate), and among all participants who are RBC transfusion-independent at baseline (maintenance rate).
  • Platelet Transfusion Independence Rate (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Safety Run-in Cohorts 1 and 3: First dose date up to 24 months; Safety Run-in Cohort 2: First dose date up to 12 months; Phase 2 Cohorts 1 and 3: First dose date up to 24 months; Phase 2 Cohort 2: First dose date up to 12 months ]
    The platelet transfusion independence rate is the percentage of participants who have a 56-day or longer period with no platelet transfusions at any time between the date of the first dose and discontinuation of study treatment among all participants who are platelet transfusion-dependent at baseline, defined as having received a platelet transfusion within the 8 weeks prior to the first dose of study treatment (conversion rate), and among all participants who are platelet transfusion independent at baseline (maintenance rate).
  • Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) According to the NCI CTCAE Version 5.0 (Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Phase 2 Cohorts 1 and 3: First dose date up to 24 months plus 70 days; Phase 2 Cohort 2: First dose date up to 12 months plus 70 days ]
    A treatment-emergent adverse event (TEAE) will be defined as any AE that begins on or after the date of first dose of study drug up to the date of last dose of study drug plus 70 days.
  • Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities According to the NCI CTCAE Version 5.0 (Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Phase 2 Cohorts 1 and 3: First dose date up to 24 months plus 70 days; Phase 2 Cohort 2: First dose date up to 12 months plus 70 days ]
    Treatment-emergent laboratory abnormalities will be defined as values that increase at least 1 toxicity grade from baseline at any time point postbaseline and will be summarized by treatment group. If baseline data are missing, then any graded abnormality (ie, at least Grade 1) will be considered treatment emergent. All toxicities will be graded according to the NCI CTCAE Version 5.0.
  • Plasma Concentration of Magrolimab in Combination with Anti-leukemia Therapy (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Within 72 hours predose & 12 hours postdose before subsequent doses of magrolimab on Days 1 & 8 of Cycle 1, Day 1 of Cycles 2, 3, 5, 7, 10, 13, and end of treatment (EOT) (within 7 days after last dose of magrolimab or EOT decision); Cycle length=28 days ]
    Plasma concentrations of magrolimab in combination with venetoclax and azacitidine; mitoxantrone, etoposide, and cytarabine; or CC-486. Cycle length is 28 days.
  • Immunogenicity of Magrolimab in Combination with Anti-leukemia Therapy (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Within 72 hours predose & 12 hours postdose before subsequent doses of magrolimab on Day 1 of Cycles 1, 2, 3, 5, 7, 10, 13, and end of treatment (EOT) (within 7 days after last dose of magrolimab or EOT decision); Cycle length=28 days ]
    Antidrug antibody assessment will be performed using a validated assay following a 3-tiered approach: screening, confirmatory, and titer testing. Cycle length is 28 days.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 1, 2021)
  • Overall Response Rate (ORR) (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    Overall response rate is the percentage of participants who achieve complete remission (CR) [Complete remission without minimal residual disease (CRMRD-) or complete remission with positive or unknown minimal residual disease (CRMRD+/unk)], complete remission with incomplete hematologic recovery (CRi), complete remission with partial hematologic recovery (CRh), partial remission (PR), or morphologic leukemia-free state (MLFS) as determined by the investigator based on prespecified criteria while on study prior to initiation of any new anti-cancer therapy. Assessment of leukemia response inpatients with AML will be conducted based on the ELN recommendations for AML.
  • Completed Remission Rate (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The complete remission (CR) rate is the percentage of patients who achieve CR (CRMRD- or CRMRD+/unk) as determined by the investigator based on prespecified criteria while on study prior to initiation of any new anti-cancer therapy. Assessment of leukemia response inpatients with AML will be conducted based on the ELN recommendations for AML.
  • Complete Remission without Minimal Residual Disease Rate (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The Complete Remission without Minimal Residual Disease (CRMRD-) rate is the percentage of participants who achieve a CRMRD- as determined by the investigator based on prespecified criteria while on study prior to initiation of any new anti-cancer therapy. Assessment of leukemia response inpatients with AML will be conducted based on the ELN recommendations for AML.
  • Complete Remission or Complete Remission with Partial Hematologic Recovery Rate (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The complete remission or complete remission with partial hematologic recovery (CR/CRh) rate is the percentage of participants who achieve CR (CRMRD- or CRMRD+/unk) or CRh as determined by the investigator based on prespecified criteria while on study prior to initiation of any new anti-cancer therapy. Assessment of leukemia response inpatients with AML will be conducted based on the ELN recommendations for AML.
  • Duration of Response (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The duration of response (DOR) is measured from the time assessment criteria that are met for CR (CRMRD- or CRMRD+/unk), CRi, CRh, PR, or MLFS, whichever is first recorded, until the first date of AML relapse, progressive disease, or death.
  • Duration of Complete Remission (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The duration of CR is measured from the time the assessment criteria are first met for CR (CRMRD- or CRMRD+/unk) until the first date of AML relapse or death.
  • Duration of Complete Remission or Complete Remission with Incomplete Hematologic Recovery (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The duration of CR/CRi is measured from the time the assessment criteria are first met for CR (CRMRD- or CRMRD+/unk) or CRi until the first date of AML relapse or death.
  • Duration of Complete Remission or Complete Remission with Partial Hematologic Recovery (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    The duration of CR/CRh is measured from the time the assessment criteria are first met for CR (CRMRD- or CRMRD+/unk) or CRh until the first date of AML relapse or death.
  • Event-Free Survival (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) [ Time Frame: First dose date up to 3 years ]
    Event-free survival (EFS) is defined as the time from the date of the first dose of study treatment to the earliest date of documented relapse from CR/CRi, treatment failure (defined as failure to achieve CR/CRi before the fifth cycle of magrolimab+venetoclax+azacitidine in Phase 2 Cohort 1 and before the third cycle of magrolimab + MEC in Phase 2 Cohort 2), or death from any cause. Cycle length is 28 days.
  • Relapse-Free Survival (Safety Run-in Cohort 3; Phase 2 Cohort 3) [ Time Frame: First dose date up to 5 years ]
    Relapse-free survival (RFS) is measured from the time of the first dose of study treatment until the first date of AML relapse or death from any cause, whichever comes first.
  • Duration of Minimal Residual Disease Negative Complete Remission or Complete Remission with Incomplete Hematologic Recovery (Safety Run-in Cohort 3; Phase 2 Cohort 3) [ Time Frame: First dose date up to 5 years ]
    The duration of MRD negative CR/CRi is measured from the time the patient achieves MRD-negative status and maintains CR/CRi until the first date of AML relapse, loss of MRD negative status, or death.
  • Overall Survival (OS) (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Safety Run-in Cohorts 1 and 2: First dose date up to 3 years; Safety Run-in Cohort 3: First dose date up to 5 years; Phase 2 Cohorts 1 and 2: First dose date up to 3 years; Phase 2 Cohort 3: First dose date up to 5 years ]
    The overall survival (OS) is measured from the date of the first dose of study treatment to the date of death from any cause.
  • Red Blood Cell Transfusion Independence Rate (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Safety Run-in Cohorts 1 and 3: First dose date up to 24 months; Safety Run-in Cohort 2: First dose date up to 12 months; Phase 2 Cohorts 1 and 3: First dose date up to 24 months; Phase 2 Cohort 2: First dose date up to 12 months ]
    The red blood cell (RBC) transfusion independence rate is the percentage of participants who have a 56-day or longer period with no RBC transfusion at any time between the date of the first dose and discontinuation of study treatment among all participants who are RBC transfusion-dependent at baseline, defined as having received an RBC or whole blood transfusion within the 8 weeks prior to the first dose of study treatment (conversion rate), and among all participants who are RBC transfusion-independent at baseline (maintenance rate).
  • Platelet Transfusion Independence Rate (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Safety Run-in Cohorts 1 and 3: First dose date up to 24 months; Safety Run-in Cohort 2: First dose date up to 12 months; Phase 2 Cohorts 1 and 3: First dose date up to 24 months; Phase 2 Cohort 2: First dose date up to 12 months ]
    The platelet transfusion independence rate is the percentage of participants who have a 56-day or longer period with no platelet transfusions at any time between the date of the first dose and discontinuation of study treatment among all participants who are platelet transfusion-dependent at baseline, defined as having received a platelet transfusion within the 8 weeks prior to the first dose of study treatment (conversion rate), and among all participants who are platelet transfusion independent at baseline (maintenance rate).
  • Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) According to the NCI CTCAE Version 5.0 (Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Phase 2 Cohorts 1 and 3: First dose date up to 24 months plus 30 days; Phase 2 Cohort 2: First dose date up to 12 months plus 30 days ]
    A treatment-emergent adverse event (TEAE) will be defined as any AE that begins on or after the date of first dose of study drug up to the date of last dose of study drug plus 30 days.
  • Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities According to the NCI CTCAE Version 5.0 (Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Phase 2 Cohorts 1 and 3: First dose date up to 24 months plus 30 days; Phase 2 Cohort 2: First dose date up to 12 months plus 30 days ]
    Treatment-emergent laboratory abnormalities will be defined as values that increase at least 1 toxicity grade from baseline at any time point postbaseline and will be summarized by treatment group. If baseline data are missing, then any graded abnormality (ie, at least Grade 1) will be considered treatment emergent. All toxicities will be graded according to the NCI CTCAE Version 5.0.
  • Plasma Concentration of Magrolimab in Combination with Anti-leukemia Therapy (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Within 72 hours predose & 12 hours postdose before subsequent doses of magrolimab on Days 1 & 8 of Cycle 1, Day 1 of Cycles 2, 3, 5, 7, 10, 13, and end of treatment (EOT) (within 7 days after last dose of magrolimab or EOT decision); Cycle length=28 days ]
    Plasma concentrations of magrolimab in combination with venetoclax and azacitidine; mitoxantrone, etoposide, and cytarabine; or CC-486. Cycle length is 28 days.
  • Immunogenicity of Magrolimab in Combination with Anti-leukemia Therapy (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) [ Time Frame: Within 72 hours predose & 12 hours postdose before subsequent doses of magrolimab on Day 1 of Cycles 1, 2, 3, 5, 7, 10, 13, and end of treatment (EOT) (within 7 days after last dose of magrolimab or EOT decision); Cycle length=28 days ]
    Antidrug antibody assessment will be performed using a validated assay following a 3-tiered approach: screening, confirmatory, and titer testing. Cycle length is 28 days.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Magrolimab Combinations in Participants With Myeloid Malignancies
Official Title  ICMJE A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients With Myeloid Malignancies
Brief Summary The primary objectives of this study are to evaluate the safety, tolerability and to determine the recommended Phase 2 dose (RP2D) of magrolimab (Mag) in combination with the anti-leukemia therapies of venetoclax (Ven) and azacitidine (Aza) (Cohort 1), mitoxantrone, etoposide, and cytarabine (MEC) (Cohort 2) and CC-486 (Cohort 3) respectively in participants with acute myeloid leukemia (AML), to evaluate the efficacy of magrolimab in combination with the anti-leukemia therapies as determined by the rate of complete remission (CR) (Phase 2 Cohorts 1 and 2), and/or complete remission with incomplete hematologic recovery (CRi) (CR/CRi) (Phase 2 Cohort 2) and to evaluate the efficacy of magrolimab in combination with anti-leukemia therapy CC-486 as determined by the minimal residual disease (MRD) negative CR rate (Phase 2 Cohort 3).
Detailed Description

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 will be enrolled into the corresponding Phase 2 cohorts;

  • Phase 2 Cohort 1 (1L Unfit UML 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
After completion of Safety Run-in cohorts and identification of the RP2D for the specific cohorts, participants will be enrolled to the corresponding Phase 2 cohorts.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Myeloid Malignancies
Intervention  ICMJE
  • Biological: Magrolimab
    Administered intravenously
    Other Name: GS-4721
  • Drug: 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
  • Drug: 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
  • Drug: Mitoxantrone
    Administered intravenously, 8 mg/m^2 on Days 1-5 during Cycle 1 to Cycle 3
  • Drug: Etoposide
    Administered intravenously, 100 mg/m^2 on Days 1-5 during Cycle 1 to Cycle 3
  • Drug: Cytarabine
    Administered intravenously, 1000 mg/m^2 on Days 1-5 during Cycle 1 to Cycle 3
  • Drug: CC-486
    Administered orally, 300 mg on Days 1-14 during each cycle
    Other Name: Onureg
Study Arms  ICMJE
  • Experimental: Safety Run-in Cohort 1 (1L Unfit AML Mag+Ven+Aza)
    Participants with newly diagnosed untreated AML who are ineligible for intensive induction chemotherapy will receive magrolimab, venetoclax and azacitidine.
    Interventions:
    • Biological: Magrolimab
    • Drug: Azacitidine
    • Drug: Venetoclax
  • Experimental: Safety Run-in Cohort 2 (R/R AML Mag+MEC)
    Participants with relapsed or refractory (r/r) AML will receive magrolimab and MEC.
    Interventions:
    • Biological: Magrolimab
    • Drug: Mitoxantrone
    • Drug: Etoposide
    • Drug: Cytarabine
  • Experimental: Safety Run-in Cohort 3 (Post-Chemo Maintenance Mag+CC-486)
    Participants with newly diagnosed AML who are in complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) with minimal residual disease (MRD) positivity following intensive chemotherapy will receive magrolimab and CC-486.
    Interventions:
    • Biological: Magrolimab
    • Drug: CC-486
  • Experimental: Phase 2 Cohort 1 (1L Unfit AML Mag+Ven+Aza)
    Participants with newly diagnosed untreated AML who are ineligible for intensive induction chemotherapy will receive magrolimab at the recommended Phase 2 dose (RP2D) determined in the Safety run-in cohort 1, venetoclax and azacitidine.
    Interventions:
    • Biological: Magrolimab
    • Drug: Azacitidine
    • Drug: Venetoclax
  • Experimental: Phase 2 Cohort 2 (R/R AML Mag+MEC)
    Participants with relapsed or refractory (r/r) AML will receive magrolimab at the RP2D determined in the Safety run-in cohort 2 and MEC.
    Interventions:
    • Biological: Magrolimab
    • Drug: Mitoxantrone
    • Drug: Etoposide
    • Drug: Cytarabine
  • Experimental: Phase 2 Cohort 3 (Post-Chemo Maintenance Mag+CC-486)
    Participants with newly diagnosed AML who are in complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) with minimal residual disease (MRD) positivity following intensive chemotherapy will receive magrolimab at the RP2D determined in the Safety run-in cohort 3 and CC-486.
    Interventions:
    • Biological: Magrolimab
    • Drug: CC-486
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 1, 2021)
164
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2026
Estimated Primary Completion Date June 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

All Individuals:

  • 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 ≥ 9.5 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 AML Mag+Ven+Aza)]:

  • 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
  • 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 Mag+MEC)]:

  • Individuals with histological confirmation of AML by WHO criteria who are refractory to or have experienced first relapse after initial intensive chemotherapy
  • At least 3 weeks must have elapsed since any prior systemic or targeted anti-leukemia agents. NOTE: Localized non-central nervous system (CNS) radiotherapy, hydroxyurea, oral etoposide, 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.

Safety Run-in Cohort 3 and Phase 2 Cohort 3 (Post-chemo Maintenance Mag+CC-486):

  • Individuals with histological confirmation of AML by WHO criteria who achieved a CR or 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

Key Exclusion Criteria:

  • Positive serum pregnancy test
  • 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-AML therapies and who are in complete remission for over 3 years. 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

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Gilead Clinical Study Information Center 1-833-445-3230 (GILEAD-0) GileadClinicalTrials@gilead.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04778410
Other Study ID Numbers  ICMJE GS-US-546-5920
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Gilead Sciences
Study Sponsor  ICMJE Gilead Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Gilead Study Director Gilead Sciences
PRS Account Gilead Sciences
Verification Date November 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP