Recruiting Has Begun in Trial to Determine Magrolimab Efficacy in R/R AML

Magrolimab plus antileukemia therapies is currently being tested in a phase 2 trial to determine the efficacy for patients with first-line relapsed/refractory or maintenance treatment of acute myeloid leukemia, according to a presentation from the 2021 American Society of Hematology.

Magrolimab is a monoclonal antibody that is designed to block the macrophage inhibitory immune checkpoint cluster of differentiation 47 (CD47). CD47 is a ‘do not eat me’ signal that is overexpression on tumor cells, preventing phagocytosis of tumor cells. Chemotherapy in combination with hypomethylating agents synergize with magrolimab by inducing ‘eat me’ singles on leukemic blasts, thus enhancing phagocytosis.

Previous studies have found that magrolimab plus azacitidine has an objective response rate (ORR) of 65% and a complete remission rate or complete remission with incomplete hematologic recovery (Cri) rate of 56% in untreated acute myeloid leukemia. In patients with remission, maintenance therapy with oral azacitidine improved overall survival and reduced relapse risk. However, relapse risk remains high.

The phase 2 study (NCT04778410) aims to determine the efficacy, safety, and tolerability of magrolimab in combination with different antileukemia therapies in multiple settings, including both the first line and maintenance space. The primary end points of the study include rate of complete remission, minimal residual disease, percentage of participants experiencing dose-limiting toxicities, percentage of patients experiencing treatment-emergent adverse events, and the percentage of patients experiencing laboratory abnormalities.

Secondary end points include overall response rate, complete remission, duration of response, duration of complete remission, event-free survival, relapse-free survival, minimal residual disease, duration of minimal residual disease negativity, overall survival, red blood cell transfusion independence rate, platelet transfusion independence rate, and immunogenicity of the combinations.

During the open-label study, 3 safety run-ins will be conducted with a corresponding phase 2 trial. Cohort 1 will be composed of patients with newly diagnosed, previously untreated AML, who are ineligible for immunochemotherapy. Patients in this cohort will receive a combination of magrolimab plus venetoclax plus azacitidine. The safety run in will be made up of 6 patients, and the phase 2 arm will enroll 40. During phase 2, treatment will continue until progressive disease, unacceptable toxicity, or lox of clinical benefit.

Cohort 2 will be made up of patients with AML who are relapsed or refractory of induction immunochemotherapy. Patients in those cohort will receive magrolimab plus mitoxantrone, etoposide, and cytarabine (MEC). The safety run-in will be made up of 6 patients and the phase 2 arm will enroll 30 patients. Patients in this arm will receive 2 to 3 cycles of MEC and up to 12 months of magrolimab.

Cohort 3 will include patients with AML in complete remission or Cri after immunochemotherapy who are minimal residual disease positive. Patients in this cohort will receive magrolimab plus CC-486. The safety run in will include 6 patients and the phase 2 arm will enroll 40 patients. Treatment will be continued until progressive disease, unacceptable toxicity, or loss of clinical benefit. 

In order to participate, patients must have a white blood cell count of ≤ 20 x 103/uL and a hemoglobin of ≥9 g/dL prior to the first dose. Patients must also have adequate renal and live functioning and pretreatment blood crossmatch must be completed.

In order to be included in cohort 1, patients must have untreated AML that is ineligible for standard immunotherapy either due to age, have an ECOG score of 2 to 3, lung carbon monoxide-diffusing capacity of ≤65% or FEC ≤65%, LVEF ≤50%, Clcr ,45 mL/min. If patients are 75 years of age or older, te must have an ECOG performance score of 0 to 2. If they are between 18 and 74, patients must have an ECOF performance score of 0 to 3.

In order to be included in cohort 2, it must be at least 3 weeks since last prior systemic or targeted antileukemia drug. Patients must also have an ECOG performance score of 0 to 2 and must lack systematic congestive heart failure or clinically significant cardiac arrythmias.

In order to be included in cohort 3, patients must not be a candidate for hematopoietic stem cell transplantation within 1 year of achievement of initial remission.

Key exclusion criteria for all cohorts include prior treatment with CD47, a diagnosis of acute promyelocytic leukemia, significant disease or medical conditions, or have a diagnosis of a second malignancy.

Reference

Vyas P, Daver N, Chao M, et al. Phase 2, open-label, multiarm, multicenter study to evaluate magrolimab combined with antileukemia therapies for first-line, relapsed/refractory, or maintenance treatment of acute myeloid leukemia. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3793.