BACKGROUND: Myelodysplastic syndrome (MDS) is a clonal myeloid disor-der characterized by cytopenia and ineffective hematopoiesis. MDS primarily affects older individuals, with the median age of diagnosis at70 years. Prognosis and treatment decisions are guided by the revised International Prognostic Scoring System (IPSS-R) criteria. Patients with intermediate, high, and very high risk MDS (HR-MDS) have a median overall survival (OS) of 0.8 to 3.7 years. Despite the high unmet need in this patient population, azacitidine (AZA) is the only approved therapy forHR-MDS that has improved OS in clinical trials to date. However, AZA treatment is characterized by low complete response (CR) rates (10% to17%) with limited OS (< 2 years ), indicating a need for alternative therapies. Magrolimab is a first-in-class monoclonal antibody that blocks the macrophage inhibitory immune checkpoint CD47, a “do not eat me” signal overexpressed on tumor cells. Binding of magrolimab to CD47 leads to phagocytosis of tumor cells. AZA increases expression of tumor cellprophagocytic “eat me” signals, facilitating synergy with magrolimab. In an ongoing Phase 1b study, the combination of magrolimab + AZA led to high response rates (overall response rate 91%, with a CR of 42%) and an acceptable safety profile without significant immune-related adverse events. ENHANCE (NCT04313881) is a Phase 3 trial comparing the efficacy and safety of magrolimab + AZA with that of AZA + placebo in previously untreated patients with HR-MDS.
TRIAL DESIGN/ DESIGN AND METHODS: Patients ≥18 years old with previously untreated intermediate to very high risk MDS by IPSS-R are eligible for ENHANCE. Randomization is 1:1 to magrolimab + AZA or AZA+ placebo with no crossover allowed. Magrolimab or placebo is administered intravenously with an initial 1 mg/kg priming dose to mitigate on-target anemia. An intrapatient dose-escalation regimen up to 30 mg/kgis then administered through Cycle 1, 30 mg/kg weekly dosing in Cycle2, and 30 mg/kg once every 2 weeks in Cycle 3 and beyond. AZA is administered per regional prescribing information. Patients may remain on treatment until disease progression, relapse, loss of clinical benefit, or until unacceptable toxicities occur. The 2 primary efficacy endpoints are CR rate and OS. For patients undergoing allogeneic stem cell transplantation (ASCT), data for the CR rate will be censored at the time of ASCT, and OS will be censored at the last known alive date. Secondary efficacy endpoints include red blood cell transfusion independence rate, event-free survival, minimal residual disease-negative rate, time to acute myeloid leukemia transformation, and patient-reported Functional Assessment of Cancer Therapy Anemia response rate. Biomarkers of immune cell recruitment, immune cell signaling, and bone marrow penetration of magrolimab will also be explored.
STATUS: As of June 2021, there are 62 sites active globally, including 41 distributed across the US. Patient enrollment began in September 2020, and as of June 2021, 144 patients have been enrolled in the trial. Planned enrollment is approximately 520 patients globally, and accrual is ongoing.
