MAGROLIMAB + AZACITIDINE VERSUS AZACITIDINE + PLACEBO IN UNTREATED, HIGHER-RISK (HR) MYELODYSPLASTIC SYNDROME: THE PHASE 3, RANDOMIZED, ENHANCE STUDY
Author(s): ,
Guillermo Garcia-Manero
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Naval G. Daver
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Jin Xu
Affiliations:
Gilead Sciences, Inc.,Foster City,United States
,
Mark Chao
Affiliations:
Gilead Sciences, Inc.,Foster City,United States
,
Trisha Chung
Affiliations:
Gilead Sciences, Inc.,Foster City,United States
,
Anderson Tan
Affiliations:
Gilead Sciences, Inc.,Foster City,United States
,
Vivian Wang
Affiliations:
Gilead Sciences, Inc.,Foster City,United States
,
Andrew H. Wei
Affiliations:
The Alfred Hospital and Monash University,Melbourne,Australia
,
Paresh Vyas
Affiliations:
University of Oxford,Oxford,United Kingdom
David A. Sallman
Affiliations:
Moffitt Cancer Center,Tampa,United States
EHA Library. Garcia-Manero G. 06/09/21; 324299; PB1624
Dr. Guillermo Garcia-Manero
Dr. Guillermo Garcia-Manero
Contributions
Abstract

Abstract: PB1624

Type: Publication Only

Session title: Myelodysplastic syndromes - Clinical

Background
Myelodysplastic syndrome (MDS) is a clonal myeloid disorder characterized by cytopenia and ineffective hematopoiesis. The median age of diagnosis is approximately 70 years of age, and prognosis and treatment are guided by the Revised International Prognostic Scoring System (IPSS-R) criteria. Patients with intermediate, high, and very high risk 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 for HR-MDS that has improved OS in clinical trials to date. However, these agents lead to low complete response (CR) rates (10-17%) with limited OS (<2 years), indicating a need for alternative therapy. Magrolimab (Magro) 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 Magro to CD47 leads to phagocytosis of tumor cells. AZA increases expression of prophagocytic “eat me” signals, facilitating synergy with Magro. In an ongoing phase 1b study, the combination of Magro+AZA led to high response rates (objective response rate 91%, with a CR of 42%) and an acceptable safety profile without significant immune-related adverse events. 

Aims
ENHANCE (NCT04313881) is a phase 3 trial to compare the efficacy and safety of Magro+AZA with that of AZA+placebo (PBO) in previously untreated patients with HR-MDS.

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 Magro+AZA or AZA+PBO with no crossover allowed. Magro or PBO is administered intravenously (IV) with an initial 1 mg/kg priming dose to mitigate on-target anemia. An intrapatient dose-escalation regimen up to 30 mg/kg is then administered through Cycle 1, 30 mg/kg weekly dosing in Cycle 2, with 30 mg/kg dosing 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. Two 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 (FACT)−Anemia response rate. Biomarkers of immune cell recruitment, immune cell signaling, and bone marrow penetration of Magro will also be explored. Planned enrollment is approximately 520 patients globally, which began in September 2020. 

Results
Trial in progress.

Conclusion
Accrual is ongoing.

Keyword(s): Antibody, Azacitidine, High risk, Phase III

Abstract: PB1624

Type: Publication Only

Session title: Myelodysplastic syndromes - Clinical

Background
Myelodysplastic syndrome (MDS) is a clonal myeloid disorder characterized by cytopenia and ineffective hematopoiesis. The median age of diagnosis is approximately 70 years of age, and prognosis and treatment are guided by the Revised International Prognostic Scoring System (IPSS-R) criteria. Patients with intermediate, high, and very high risk 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 for HR-MDS that has improved OS in clinical trials to date. However, these agents lead to low complete response (CR) rates (10-17%) with limited OS (<2 years), indicating a need for alternative therapy. Magrolimab (Magro) 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 Magro to CD47 leads to phagocytosis of tumor cells. AZA increases expression of prophagocytic “eat me” signals, facilitating synergy with Magro. In an ongoing phase 1b study, the combination of Magro+AZA led to high response rates (objective response rate 91%, with a CR of 42%) and an acceptable safety profile without significant immune-related adverse events. 

Aims
ENHANCE (NCT04313881) is a phase 3 trial to compare the efficacy and safety of Magro+AZA with that of AZA+placebo (PBO) in previously untreated patients with HR-MDS.

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 Magro+AZA or AZA+PBO with no crossover allowed. Magro or PBO is administered intravenously (IV) with an initial 1 mg/kg priming dose to mitigate on-target anemia. An intrapatient dose-escalation regimen up to 30 mg/kg is then administered through Cycle 1, 30 mg/kg weekly dosing in Cycle 2, with 30 mg/kg dosing 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. Two 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 (FACT)−Anemia response rate. Biomarkers of immune cell recruitment, immune cell signaling, and bone marrow penetration of Magro will also be explored. Planned enrollment is approximately 520 patients globally, which began in September 2020. 

Results
Trial in progress.

Conclusion
Accrual is ongoing.

Keyword(s): Antibody, Azacitidine, High risk, Phase III

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