This phase I trial studies how well the combination of magrolimab works with azacitidine after a donor stem cell transplant (allogeneic hematopoietic cell transplantation) in treating patients with high-risk acute myeloid leukemia or myelodysplastic syndrome. Magrolimab is a type of protein called an antibody. It is designed to target and block a protein called CD47. CD47 is present on cancer cells and is used by cancer cells to protect themselves from the body's immune system. Blocking CD47 with magrolimab may enable the body's immune system to find and destroy the cancer cells. Azacitidine is a chemotherapy drug that may prevent the return of acute myeloid leukemia or myelodysplastic syndrome by working in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Combining magrolimab and azacitidine may kill more cancer cells after allogeneic hematopoietic cell transplantation in patients with high-risk acute myeloid leukemia or myelodysplastic syndromes.
PRIMARY OBJECTIVE: I. Establish safety/feasibility and determine the recommended phase 2 dose (RP2D) of magrolimab in combination with a fixed dose of azacitidine when given as the maintenance therapy after reduced intensity conditioning allogeneic hematopoietic cell transplantation (HCT), in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). SECONDARY OBJECTIVES: I. Estimate overall survival (OS), progression-free survival (PFS), cumulative incidence (CI) of relapse/progression, non-relapse mortality (NRM) at +100 days and 1-year post- maintenance therapy. II. Estimate CI of acute graft-versus-host disease (GVHD) at 180 days post HCT, and chronic GVHD at one-year post-HCT. III. Longitudinally characterize minimal residual disease (MRD+) status in patients receiving maintenance therapy. IV. Feasibility of receiving magrolimab in combination with azacitidine as maintenance therapy in this patient population. EXPLORATORY OBJECTIVES: I. Characterize the presence and level of GVHD biomarkers and inflammatory cytokines in the first 100 days from the start of maintenance therapy. II. Assess the possible correlation between chimerism kinetics by AlloHeme assay (per next generation sequencing \[NGS\] assay) and post-HCT relapse. III. Describe kinetics of immune cell recovery and macrophage activation in the first-year post-HCT. IV. Assess health related quality of life (QoL) and symptoms on days 1, 60, 90 and 180 after starting maintenance therapy. OUTLINE: This is a dose-escalation study of magrolimab (MRD- patients only), followed by a dose-expansion study (MRD- and MRD+ patients). Patients undergo allo HCT per standard of care. Patients then receive magrolimab intravenously (IV) and azacitidine IV on study. Patients undergo echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) during screening and blood sample collection and bone marrow biopsy and aspirate throughout the study.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Undergo allo HCT per standard of care
Given IV
Undergo blood sample collection
Undergo bone marrow biopsy and aspirate
Undergo bone marrow biopsy and aspirate
Undergo ECHO
Given IV
Undergo MUGA
Ancillary studies
Incidence of dose-limiting toxicities
Dose limiting toxicities (DLT) are defined as any of the following events that are attributed at least possibly due to study regimen and occur from start of magrolimab (day +1) to the end of the first cycle of magrolimab maintenance (day +85 +/-7): Death, grade 3-4 non-hematological toxicities per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE 5.0), grade 4 hematological toxicities per NCI CTCAE 5.0 that last for more than 21 days. Will utilize the revised National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 for adverse events reporting.
Time frame: The evaluation period of DLT is from starting study regimen (day + 1) to the first observation of DLT, or the end of the first cycle of Magrolimab maintenance (day +85) with a grace period of ±7days, whichever comes first. (Each cycle is 28 days)
Maximum tolerated dose (MTD) and recommended phase 2 dose (RPD) of magrolimab
Will use the time-to-event Bayesian optimal interval (TITE-BOIN) design \[1\] to find the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D).
Time frame: The evaluation period of DLT is from starting study regimen (day + 1) to the first observation of DLT, or the end of the first cycle of Magrolimab maintenance (day +85) with a grace period of ±7days, whichever comes first. (Each cycle is 28 days)
Overall survival
Time frame: Time period from start of protocol therapy to death regardless of cause, assessed up to 6 years
Progression free survival
Time frame: Time from start of protocol therapy to relapse/progression, or death, whichever comes first, assessed up to 6 years
Cumulative incidence of relapse/progression (CIR)
Will be estimated using the cumulative incidence.
Time frame: Time of start of treatment to time of relapse/progression, assessed up to 6 years
Cumulative incidence of on-relapse mortality (NRM)
Will be estimated using the cumulative incidence.
Time frame: Time of start of treatment to non-disease related death, assessed up to 6 years
Cumulative incidence of acute graft versus host disease (aGvHD) of grades 2-4 and 3-4
Will be assessed by documented or biopsy proven aGvHD and graded according to the Mount Sinai Acute GVHD International Consortium (MAGIC) grading. Will be estimated using the cumulative incidence curve.
Time frame: Time of start of treatment to first documented/biopsy proven acute GVHD onset date, at 180 days post transplant
Cumulative incidence of chronic graft versus host disease (cGvHD)
Will be assessed by documented or biopsy proven cGvHD and scored according to the National Institutes of Health (NIH) Consensus Staging. Disease relapse/progression or NRM is considered competing risk events. cGvHD will be censored at time of last follow-up if patients remain alive and free of relapse/progression. cGvHD will be estimated using the cumulative incidence curve.
Time frame: Time of start of treatment to first documented/biopsy proven chronic GVHD onset date, assessed at 1 year post transplant
Minimal residual disease
Will be assessed from bone marrow aspirates collected on days 30, 100, and 180 post HCT.
Time frame: Assessed up to 6 years
Completion of planned therapy
Feasibility is defined as ability to complete at least 30% of the planned therapy.
Time frame: Assessed up to 6 years
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