Magrolimab in Combination with Azacitidine After Allogeneic HCTin Treating Patients with High-Risk AML or MDS

A Multi-Center, Phase 1 Trial of Combining Anti-CD47 Antibody (Magrolimab) with Azacitidine As Post-Transplant Maintenance Therapy in Patients Who Underwent Allogeneic Hematopoietic Cell Transplantation for Treatment of High-Risk AML or MDS

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.

Inclusion Criteria:

• Documented informed consent of the patient and/or legally authorized representative (done within 30 days of HCT day 0).

• Agreement to allow the use of archival tissue from diagnostic tumor biopsies.

  • If unavailable, exceptions may be granted with study principal investigator (PI) approval.

• Age: 18-75 years old.

• Eastern Cooperative Oncology Group =< 2.

• Patients who are scheduled to undergo allogeneic HCT for AML with high-risk cytogenetics per European Leukemia Net (ELN) or MDS with International Prognostic Scoring System (IPSS) of intermediate 2 with poor risk cytogenetics or molecular markers. OR patients with MRD+ disease OR active disease with < 10% blast at the time of HCT.

• Patients who are scheduled to undergo their first or second HCT with reduced intensity conditioning regimen (any reduced intensity conditioning regimen per institutional standards is allowed), and regardless of GVHD prophylactic regimen.

• Allogeneic transplant regardless of donor type (matched, mismatched, haploidentical, etc.) or graft source (bone marrow or mobilized peripheral blood stem cells) are included.

• Pre-HCT exposure to anti-CD47 of hypomethylating agent (HMA) is allowed if no progression on therapy has been documented.

• Absolute neutrophil count (ANC) >= 1.5 (without the use of granulocyte-colony stimulating factor [GCSF] for last 2 weeks) (To be performed within 45 days prior to transplant unless otherwise stated).

  • NOTE: Transfusion (Red blood cells [RBC] or platelet) to achieve the above-mentioned counts is allowed.

• Platelet count >= 50K (To be performed within 45 days prior to transplant unless otherwise stated).

  • NOTE: Transfusion (RBC or platelet) to achieve the above-mentioned counts is allowed.
  • NOTE: Complete blood count (CBC) should be done within 2 weeks of day 1 of the protocol.

• Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) (To be performed within 45 days prior to transplant unless otherwise stated).

• Aspartate transaminase (AST) =< 1.5X ULN (To be performed within 45 days prior to transplant unless otherwise stated).

• Alanine transaminase (ALT) =< 1.5 X ULN (To be performed within 45 days prior to transplant unless otherwise stated).

• Creatinine clearance of >= 60 mL/min per 24-hour urine test or the Cockcroft-Gault formula (To be performed within 45 days prior to transplant unless otherwise stated).

• Left ventricular ejection fraction (LVEF) >= 45% (To be performed within 45 days prior to transplant unless otherwise stated).

• If able to perform pulmonary function tests: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) (diffusion capacity) >= 50% of predicted (corrected for hemoglobin). If unable to perform pulmonary function tests: oxygen (O2) saturation > 92% on room air. (To be performed within 45 days prior to transplant unless otherwise stated).

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. (To be performed within 45 days prior to transplant unless otherwise stated).

• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy.

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).

Exclusion Criteria:

• Patient who underwent more than 2 allogeneic HCTs.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents (azacitidine or magrolimab).
• Females only: Pregnant or breastfeeding.
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures.
• Known inherited or acquired bleeding disorders.
• Clinical suspicion of active central nervous system (CNS) involvement by MDS.
• Significant medical diseases or conditions, including but not limited to, acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes, significant active infection and congestive heart failure (CHF) New York Heart Association (NYHA) class 3-4.
• Known or active hepatitis B or C infection or human immunodeficiency virus (HIV) infection in medical history.
• Prospective patients who, in the opinion of the principal investigator (PI), may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).