Study of Magrolimab Combinations in Participants With Myeloid Malignancies

Study Overview
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Brief Summary
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The goal of this clinical study is to learn more about the safety and dosing of the study drug, magrolimab (Mag), in combination with anti-leukemia therapies in participants with acute myeloid leukemia (AML).

Detailed Description
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The anti-leukemia therapies are defined as follows: 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.

Official Title
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A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients With Myeloid Malignancies

Conditions
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Myeloid Malignancies

Intervention / Treatment
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* Drug: Magrolimab
* Drug: Azacitidine
* Drug: Venetoclax
* Drug: Mitoxantrone
* Drug: Etoposide
* Drug: Cytarabine
* Drug: CC-486


Participation Criteria
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Eligibility Criteria
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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 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 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 Mag+MEC)]: Individuals with confirmation of AML by WHO criteria who are refractory to or have experienced first relapse after initial intensive chemotherapy. Note: Patients who are relapsed after or are refractory to more than 1 line of anti-AML treatment are not eligible. Patients 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. Patients 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 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-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 Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: After completion of Safety Run-in cohorts and identification of the RP2D for the specific cohorts, participants may be enrolled to the corresponding Phase 2 cohorts.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-in Cohort 1 (1L Unfit AML Mag+Ven+Aza)<br>Participants with newly diagnosed untreated AML who are ineligible for intensive induction chemotherapy will receive magrolimab, venetoclax and azacitidine. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: Azacitidine<br>* 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<br>Drug: Venetoclax<br>* 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<br>|
| Experimental: Safety Run-in Cohort 2 (R/R AML Mag+MEC)<br>Participants with relapsed or refractory (r/r) AML will receive magrolimab and MEC. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: Mitoxantrone<br>* Administered intravenously, 8 mg/m^2 on Days 1-5 during Cycle 1 to Cycle 3<br>Drug: Etoposide<br>* Administered intravenously, 100 mg/m^2 on Days 1-5 during Cycle 1 to Cycle 3<br>Drug: Cytarabine<br>* Administered intravenously, 1000 mg/m^2 on Days 1-5 during Cycle 1 to Cycle 3<br>|
| Experimental: Safety Run-in Cohort 3 (Post-Chemo Maintenance Mag+CC-486)<br>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. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: CC-486<br>* Administered orally, 300 mg on Days 1-14 during each cycle<br>* Other names: Onureg;|
| Experimental: Phase 2 Cohort 1 (1L Unfit AML Mag+Ven+Aza)<br>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. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: Azacitidine<br>* 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<br>Drug: Venetoclax<br>* 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<br>|
| Experimental: Phase 2 Cohort 2 (R/R AML Mag+MEC)<br>Participants with relapsed or refractory (r/r) AML will receive magrolimab at the RP2D determined in the Safety run-in cohort 2 and MEC. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: Mitoxantrone<br>* Administered intravenously, 8 mg/m^2 on Days 1-5 during Cycle 1 to Cycle 3<br>Drug: Etoposide<br>* Administered intravenously, 100 mg/m^2 on Days 1-5 during Cycle 1 to Cycle 3<br>Drug: Cytarabine<br>* Administered intravenously, 1000 mg/m^2 on Days 1-5 during Cycle 1 to Cycle 3<br>|
| Experimental: Phase 2 Cohort 3 (Post-Chemo Maintenance Mag+CC-486)<br>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. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: CC-486<br>* Administered orally, 300 mg on Days 1-14 during each cycle<br>* Other names: Onureg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete Remission (CR) (Phase 2 Cohorts 1 and 2) | 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. | First dose date up to 3 years | 
| Minimal Residual Disease Negative Complete Remission Rate (Phase 2 Cohort 3) | 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. | First dose date up to 5 years | 
| 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) | 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. | First dose date up to 28 days of the first dosing cycle | 
| 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) | 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. | 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 | 
| Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities According to the NCI CTCAE Version 5.0 (Safety Run-in Cohorts 1, 2, and 3) | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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. | First dose date up to 3 years | 
| Complete Remission or Complete Remission with Partial Hematologic Recovery Rate (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) | 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. | First dose date up to 3 years | 
| Duration of Response (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) | 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. | First dose date up to 3 years | 
| Duration of Complete Remission (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) | 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. | First dose date up to 3 years | 
| Duration of Complete Remission or Complete Remission with Incomplete Hematologic Recovery (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) | 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. | First dose date up to 3 years | 
| Duration of Complete Remission or Complete Remission with Partial Hematologic Recovery (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) | 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. | First dose date up to 3 years | 
| Event-Free Survival (Safety Run-in Cohorts 1 and 2; Phase 2 Cohorts 1 and 2) | 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. | First dose date up to 3 years | 
| Relapse-Free Survival (Safety Run-in Cohort 3; Phase 2 Cohort 3) | 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. | First dose date up to 5 years | 
| Minimal Residual Disease Negative Complete Remission or Complete Remission with Incomplete Hematologic Recovery (Safety Run-in Cohort 3; Phase 2 Cohort 3) | 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. | First dose date up to 5 years | 
| Duration of Minimal Residual Disease Negative Complete Remission (Safety Run-in Cohort 3; Phase 2 Cohort 3) | 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. | First dose date up to 5 years | 
| Duration of Minimal Residual Disease Negative Complete Remission or Complete Remission with Incomplete Hematologic Recovery (Safety Run-in Cohort 3; Phase 2 Cohort 3) | 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. | First dose date up to 5 years | 
| Overall Survival (OS) (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) | The overall survival (OS) is measured from the date of the first dose of study treatment to the date of death from any cause. | 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 | 
| Red Blood Cell Transfusion Independence Rate (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) | 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). | 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 | 
| Platelet Transfusion Independence Rate (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) | 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). | 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 | 
| Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) According to the NCI CTCAE Version 5.0 (Phase 2 Cohorts 1, 2, and 3) | 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. | 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 | 
| Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities According to the NCI CTCAE Version 5.0 (Phase 2 Cohorts 1, 2, and 3) | 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. | 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 | 
| 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) | Plasma concentrations of magrolimab in combination with venetoclax and azacitidine; mitoxantrone, etoposide, and cytarabine; or CC-486. Cycle length is 28 days. | 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 | 
| Immunogenicity of Magrolimab in Combination with Anti-leukemia Therapy (Safety Run-in Cohorts 1, 2, and 3; Phase 2 Cohorts 1, 2, and 3) | 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. | 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 |