A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Magrolimab versus Placebo in Combination with Venetoclax and Azacitidine in Newly Diagnosed, Previously Untreated Patients with Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy

1) Previously untreated patients with histological confirmation of AML by 2016
World Health Organization criteria who are ineligible for treatment with a
standard cytarabine and anthracycline induction regimen due to age, or
comorbidity. Patients must be considered ineligible for intensive chemotherapy,
defined by the following:
a)>= 75 years of age;
Or
b)>= 18 to 74 years of age with at least 1 of the following comorbidities:
i) Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3
ii)Diffusing capacity of the lung of carbon monoxide <= 65% or forced expiratory
volume in 1 second <= 65%
iii)Left ventricular ejection fraction <= 50%
iv)Baseline creatinine clearance >= 30 mL/min to < 45 mL/min calculated by the
Cockcroft Gault formula or measured by 24-hour urine collection
v) Hepatic disorder with total bilirubin > 1.5 ** upper limit of normal (ULN)
vi) Any other comorbidity that the investigator judges to be incompatible with
intensive chemotherapy that must be approved by the sponsor*s medical monitor
before study enrollment
2) ECOG performance status:
a)Of 0 to 2 for subjects >= 75 years of age
Or
b)Of 0 to 3 for subjects >= 18 to 74 years of age
3)Patients with white blood cell (WBC) count <= 20x10*3/µL prior to
randomization. If the patient*s WBC is > 20x10*3/µL prior to randomization, the
patient can be enrolled, assuming all other eligibility criteria are met.
However, the WBC should be <= 20x10*3/µL prior to the first dose of study
treatment and prior to each magrolimab/placebo dose during Cycle 1.
NOTE: Patients can be treated with hydroxyurea and/or leukapheresis prior to
randomization and throughout the study to reduce the WBC to <= 20x10*3/µL to
enable eligibility for study drug dosing.
4)Hemoglobin must be >= 9 g/dL prior to initial dose of study treatment based on
complete
blood count result.
NOTE: Transfusions are allowed to meet hemoglobin eligibility.
5) Patient has provided informed consent.
6) Patient is willing and able to comply with clinic visits and procedures
outlined in the study
protocol.
7) Male or female, >= 18 years of age
8) Patients must have adequate renal function as demonstrated by a creatinine
clearance >= 30 mL/min; calculated by the Cockcroft Gault formula or measured by
24-hour urine collection.
9) Adequate liver function as demonstrated by:
a)aspartate aminotransferase <= 3.0xULN
b)alanine aminotransferase <= 3.0xULN
c) total bilirubin <= 1.5xULN, or primary unconjugated bilirubin <= 3.0xULN if
patient has a documented history of Gilbert*s syndrome or genetic equivalent
d)Patients >= 18 to 74 years of age may have total bilirubin <= 3.0xULN
10) Pretreatment RBC phenotype or genotype completed
11) Male and female patients of childbearing potential who engage in
heterosexual intercourse must agree to use protocol-specified method(s) of
contraception.
12) Patients must be willing to consent to mandatory pretreatment and
on-treatment bone marrow assessments (aspirate and trephines).

1) Positive serum pregnancy test
2) Breastfeeding female
3) Known hypersensitivity to any of the study drugs, the metabolites, or
formulation excipient.
4) Patients receiving any live vaccine within 4 weeks prior to initiation of
study treatments.
5) Prior treatment with any of the following:
a) CD47 or signal regulatory protein alpha-targeting agents
b) Antileukemic therapy for the treatment of AML (eg, hypomethylating agents
(HMAs), low-dose cytarabine, and/or venetoclax), excluding hydroxyurea
NOTE: Patients with prior myelodysplastic syndrome (MDS)/myeloproliferative
neoplasm (MPN) who have not received prior HMAs or venetoclax or
chemotherapeutic agents for MDS/MPN may be enrolled in the study. Prior
treatment with MDS/MPN therapies including, but not limited to lenalidomide,
erythroid-stimulating agents, or similar red blood cell (RBC-), WBC-, or
platelet-direct therapies or growth factors is allowed for these patients.
6) Current participation in another interventional clinical study
7) Known inherited or acquired bleeding disorders
8) Patients who have received treatment with strong and/or moderate CYP3A
inducers (eg, preparations containing St. John*s wort) within 7 days prior to
the initiation of study treatments
9) Patients 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 and are unwilling to discontinue
consumption of these throughout the receipt of study drug
10) Patients who have malabsorption syndrome or other conditions that preclude
enteral route of administration
11) Clinical suspicion of or documented active central nervous system (CNS)
involvement with AML
12) Patients who have acute promyelocytic leukemia
13) 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 uncontrolled infection, and congestive
heart failure New York Heart Association Class III to IV.
14) Known history, diagnosis, or suspicion of Hemophagocytic
Lymphohistiocytosis (HLH) syndrome.
15) Second malignancy (except MDS) treated basal cell or localized squamous
skin carcinomas, localized prostate cancer, or other malignancies for which
patients are not on active anti- cancer therapies and have had no evidence of
active malignancy for at least 1 year
NOTE: Patients on maintenance therapy alone who have no evidence of active
malignancy
for at least >= 1 year are eligible.
NOTE: Localized non-CNS radiotherapy, erythroid and/or myeloid growth factors,
hormonal therapy 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.
16) Known active or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection or HIV infection in medical history within 3 months of study entry.
17) Active HBV, and/or active HCV, and/or HIV following testing at screening:
a) Patients who test positive for hepatitis B surface antigen and patients who
test positive for hepatitis B core antibody will require HBV DNA by
quantitative polymerase chain reaction (PCR) for confirmation of active disease.
b) Patients who test positive for HCV antibody will require HCV RNA
quantitative PCR for confirmation of active disease.
c) Patients who test positive for HIV antibody will require viral load testing:
those who have an undetectable viral load in the prior 3 months may be eligible
for the study.