A 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
Authors: Vyas Paresh , Daver Naval , Chao Mark , Xing Guan , Renard Camille , Ramsingh Giri , Wei Andrew H. , Sallman David A. 
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. Magrolimab induces tumor phagocytosis and eliminates leukemia stem cells. Chemotherapy and hypomethylating agents synergize with magrolimab by inducing "eat me" signals on leukemic blasts, thereby enhancing phagocytosis. Magrolimab+azacitidine (AZA) has shown encouraging clinical efficacy with an objective response rate (ORR) of 63% and a complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate of 54% in first-line acute myeloid leukemia (AML). Newly diagnosed AML patients (pts) who are ineligible for intensive chemotherapy (IC) are incurable despite the progress made with AZA+venetoclax (VEN; median overall survival [OS] 14-18 months), while AML pts with relapsed/refractory (R/R) disease after intensive regimens have a dismal prognosis. Furthermore, for pts in remission, maintenance therapy with oral AZA has improved OS and prevented relapse, although relapse rates remain high. Magrolimab combinations are being evaluated in each of these settings to improve the standard of care.
Aims: To evaluate the safety, efficacy, and tolerability of magrolimab combined with antileukemia therapies in first-line pts ineligible for IC (cohort 1), R/R pts after IC (cohort 2), and pts in CR/CRi with presence of minimal residual disease (MRD) after IC (cohort 3).
Design and Methods: This is an open-label, multiarm, multicenter study that includes 3 safety run-ins with corresponding phase 2 cohorts (NCT04778410). Pts in cohort 1 must be ≥75 years or 18-74 years with comorbidities that preclude IC. Pts in cohort 2 must have R/R AML after initial IC. Pts in cohort 3 must be ≥55 years and have achieved a CR/CRi with MRD positivity, as assessed by flow cytometry, after IC, and not be candidates for hematopoietic stem cell transplant. Each cohort will initially enroll 6 pts for 1 cycle (28 days) to assess dose-limiting toxicities and determine the recommended phase 2 dose (RP2D). Pts in cohort 1 will receive a combination of magrolimab, VEN, and AZA. Pts in cohort 2 will receive magrolimab in combination with mitoxantrone, etoposide, and cytarabine (MEC). Pts in cohort 3 will receive magrolimab with oral CC-486. All will receive magrolimab on the same schedule. In cycle 1, magrolimab will be administered intravenously (IV) as priming and ramp-up doses at 1 mg/kg on Days 1 and 4, 15 mg/kg on Day 8, and 30 mg/kg on Days 11, 15, and 22. In cycle 2, magrolimab 30 mg/kg will be administered weekly. From cycle 3 onward, magrolimab 60 mg/kg will be administered on Day 1. For cohort 1, AZA (75 mg/m 2) will be administered IV/subcutaneously on Days 1-7 or 1-5, 8, and 9 of each cycle. VEN, MEC, and CC-486 will be administered according to labeled indications. After completion of the safety run-in, additional pts will be enrolled in cohort 1 (n=40), cohort 2 (n=30), and cohort 3 (n=40) for phase 2. In phase 2, pts in cohorts 1 and 3 will receive study treatment at RP2D until disease progression, unacceptable toxicity, or loss of clinical benefit. Pts in cohort 2 will receive magrolimab with MEC for up to 3 cycles followed by magrolimab alone for a total of 12 magrolimab cycles; pts who do not achieve an objective response will discontinue after 2 cycles. In cohorts 1 and 2, the primary efficacy endpoint is the CR/CRi rate. Secondary endpoints of interest include OS, ORR, and MRD-negative CR/CRi rates. The primary efficacy endpoint in cohort 3 is the MRD-negative CR/CRi rate.
Status: Accrual is ongoing.

Disclosures
Vyas: Novartis: Honoraria; AbbVie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Daiichi Sankyo: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Daver: Abbvie: Consultancy, Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Hanmi: Research Funding; Novimmune: Research Funding; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Pfizer: Consultancy, Research Funding; Gilead Sciences, Inc.: 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. 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; Chimera Bioengineering: Current equity holder in publicly-traded company; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Bioverge: Current equity holder in publicly-traded company, 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. Xing: Gilead Sciences, Inc.: Current Employment. Renard: Alphabet: Current Employment, Current equity holder in publicly-traded company; Gilead Sciences, Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Ramsingh: Gilead Sciences, Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Wei: 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; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche AG: Research Funding; MacroGenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; 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. Sallman: Takeda: Consultancy; Magenta: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau.

OffLabel Disclosure:
Magrolimab is an investigational therapy