A Phase 3, Randomized, Open-Label Study Evaluating the Safety and Efficacy of Magrolimab in Combination with Azacitidine in Previously Untreated Patients with TP53-Mutant Acute Myeloid Leukemia
Authors: Daver Naval , Vyas Paresh , Chao Mark , Xing Guan , Renard Camille , Ramsingh Giri , Sallman David A. , Wei Andrew H. 
Published: November 2021

Abstract
Background: Magrolimab (Hu5F9-G4) is an antibody blocking CD47, a macrophage immune checkpoint and "don't eat me" signal on cancer cells, that eliminates leukemia stem cells by inducing tumor phagocytosis. Hypomethylating agents synergize with magrolimab by inducing "eat me" signals on leukemic blasts, thereby enhancing phagocytosis. Magrolimab with azacitidine (AZA) has shown encouraging activity in frontline acute myeloid leukemia (AML) unfit for intensive chemotherapy and myelodysplastic syndrome. In TP53-mutant (TP53m) AML, it demonstrated an objective response rate of 69%, complete response (CR) rate of 45%, and median overall survival (OS) of 12.9 months. The TP53 gene mutation is observed in approximately 10-15% of newly diagnosed AML and is associated with poor survival. The published first-line median OS in TP53m AML is 5-7 months, regardless of whether patients are treated with intensive chemotherapy or non-intensive approaches, such as a hypomethylating agent with venetoclax (VEN). AML patients harboring the TP53 gene mutation represent a significant unmet medical need.
Aims: To evaluate the efficacy, safety, and tolerability of magrolimab+AZA vs physician's choice of VEN+AZA or "7+3" chemotherapy in patients with previously untreated TP53m AML.
Design and Methods: This is a phase 3, randomized, open-label, multicenter study. Approximately 346 patients will be randomized (1:1) to magrolimab+AZA (investigational arm) or physician's choice of VEN+AZA or 7+3 chemotherapy, based on patient fitness (NCT04778397). Randomization will be stratified by appropriateness for non-intensive vs intensive therapy, geographic region (US vs non-US sites), and age (&lt;75 vs ≥75 years). Patients are eligible if they are ≥18 years old with histologically confirmed AML with no prior antileukemic therapy, with at least one TP53 gene mutation that is not benign or likely benign (confirmed by central laboratory) or biallelic 17p deletions (based on a locally evaluated karyotype/fluorescence in situ hybridization report). During the first 28-day cycle, patients randomized to magrolimab+AZA will receive magrolimab intravenously (IV) at a priming dose of 1 mg/kg on Days 1 and 4, 15 mg/kg on Day 8, and 30 mg/kg on Days 11, 15, and 22. Magrolimab 30 mg/kg will then be administered weekly during cycle 2 and then every other week from cycle 3 onward. For patients randomized to the VEN+AZA arm, VEN and AZA will be administered according to labeled indications. Patients treated with 7+3 chemotherapy will receive 1-2 induction cycle(s) with IV daunorubicin or idarubicin on Days 1-3 and cytarabine 100 mg/m 2 or 200 mg/m 2 on Days 1-7 followed by up to 4 consolidation cycles with high-dose cytarabine (3,000 mg/m 2). Patients receiving magrolimab+AZA or VEN+AZA will remain on treatment until disease progression, relapse, loss of clinical benefit, unacceptable toxicities, or stem cell transplant. Patients can undergo stem cell transplantation per investigator decision. The primary endpoint is OS in patients appropriate for non-intensive therapy, and the key secondary endpoint is OS in all patients.
Status: Patients will be enrolled at approximately 140 centers globally. Accrual is ongoing.

Disclosures
Daver: Gilead Sciences, Inc.: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Glycomimetics: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novimmune: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Hanmi: Research Funding; Trovagene: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Trillium: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Vyas: Novartis: Honoraria; AbbVie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Jazz: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria; Takeda: Honoraria. Chao: Gilead Sciences, Inc.: Current Employment; TigaTx: Membership on an entity's Board of Directors or advisory committees; Stanford University: Patents & Royalties; Hepatx Inc: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Iconovir Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Stanford University Medical School: Membership on an entity's Board of Directors or advisory committees; Foresite capital: Consultancy; Bioverge: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Chimera Bioengineering: Current equity holder in publicly-traded company. Xing: Gilead Sciences, Inc.: Current Employment. Renard: Gilead Sciences, Inc.: Current Employment, Current holder of individual stocks in a privately-held company; Alphabet: Current Employment, Current equity holder in publicly-traded company. Ramsingh: Gilead Sciences, Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Sallman: Syndax: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Magenta: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees. Wei: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax: Patents & Royalties; MacroGenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche AG: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

OffLabel Disclosure:
Magrolimab is an investigational therapy