GS-US-546-5920: This phase II trial is trying to understand how safe and well tolerated a new targeted cancer treatment is when combined with other standard treatments for people with leukaemiaA Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients With Myeloid Malignancies

Inclusion

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