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874 Mgta-117, an Anti-CD117 Antibody-Drug Conjugated with Amanitin, in Participants with Relapsed/Refractory Adult Acute Myeloid Leukemia (AML) and Myelodysplasia with Excess Blasts (MDS-EB): Safety, Pharmacokinetics and Pharmacodynamics Initial Findings from a Phase 1/2 Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities II
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, MDS, Biological therapies, Clinical Research, Chronic Myeloid Malignancies, Diseases, Therapies, Myeloid Malignancies, Transplantation
Monday, December 12, 2022: 3:30 PM

Peter Westervelt, MD PhD1*, Partow Kebriaei, MD2, Mark Juckett, MD3, Andrew S. Artz, MD, MS4, Onyee Chan, MD5, Philip L. McCarthy, MD6, Sherif S Farag, MD, PhD7, Anurag K. Singh, MD8, Eytan Stein, MD9, Jeffrey Humphrey, MD10, William Baeder, MPH11*, Ji Hyun Lee, MD, MPH10*, Alison Occhiuti, MS10*, Jeanie Tang, BS10*, David Santos, BS10*, Kirk Bertelsen, PhD10*, Balaji Mahender, BPharm, MS10*, Nicole Henry, BSN, RN10* and Shawn Rose, MD, PhD10

1Washington University, St. Louis, MO
2Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
3Masonic Cancer Center, University of Minnesota, Minneapolis, MN
4City of Hope, Duarte, CA
5Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
6Roswell Park Comprehensive Cancer Center, Buffalo, NY
7IU Simon Cancer Center, Indianapolis, IN
8Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
9Memorial Sloan Kettering Cancer Center, New York, NY
10Magenta Therapeutics, Cambridge, MA
11Magenta Therapeutics, Burlington, NJ

Background: MGTA-117 is a novel anti-CD117 (c-KIT)-amanitin antibody-drug conjugate (ADC) targeting CD117 that is in development as a single agent for myeloid conditioning prior to hematopoietic stem cell transplantation (HSCT). Preclinical studies show rapid and selective depletion of CD117+ stem cells and progenitor cells in bone marrow at low doses in humanized mice and nonhuman primates, rapid and predictable clearance, and potent antileukemic effects in patient-derived xenograft murine models (Lanieri et al, ASH 2020, #1044).

Objectives: To report initial results from Cohort 1 of a phase 1/2 clinical study in which MGTA-117 is administered IV as a single dose in adults with relapsed/refractory (R/R) AML or MDS-EB.

Methods: This is a multicenter, open-label study (NCT05223699). Adult participants (pts) are eligible who have a WHO-defined diagnosis of CD117+ R/R AML or MDS-EB with ≥5% bone marrow blasts (or ≥2% peripheral blasts for MDS-EB); an identified human stem cell donor; an ECOG PS ≤2; and adequate hepatic, renal, and cardiac function. The trial uses a 3+3 dose-escalation design, with an initial starting dose of 0.02 mg/kg. Overall objectives are to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), antileukemia activity, and to establish the minimum safe and biologically effective dose of MGTA-117. The observation period for dose-limiting toxicities (DLTs) is 21 days.

Results: Demographics and disease characteristics of enrolled pts are shown in the Table. In Cohort 1 (0.02 mg/kg), 4 pts were dosed; 1 pt withdrew from the study prior to completion of the DLT observation period because of disease progression and was replaced. To date, 2 pts have been dosed in Cohort 2 (0.04 mg/kg). MGTA-117 has been well tolerated to date; no DLTs, treatment-related serious adverse events (AEs), treatment-related deaths, or treatment-related hypersensitivity or anaphylactoid infusion reactions have been observed. One pt had transient related grade 1 elevations in alanine and aspartate aminotransferase levels that resolved without intervention. The remaining treatment-emergent AEs (TEAEs) were consistent with underlying disease and were considered unrelated to MGTA-117. TEAEs occurring at a frequency of >25% irrespective of causality included nausea, vomiting, tachycardia, thrombocytopenia, anemia, and liver enzyme elevation.

Maximum concentrations of MGTA-117 in Cohort 1 were reached within 1 hour post-infusion. As expected, the observed half-life was approximately 10 hours or less, and MGTA-117 concentrations were no longer measurable 48 hours after dosing in all pts (n=4). Free amanitin-containing payload was undetectable in all PK blood samples from all pts indicating stability of the ADC linker. MGTA-117 was shown to rapidly and selectively bind CD117+ cells in the blood as measured by a receptor occupancy (RO) assay, with reduction of binding to low levels within 24 hours post-dose. MGTA-117 concentrations in blood consistently mirrored RO levels over time (Figure). There was evidence supporting biologic activity of MGTA-117 in the bone marrow in 2 of 3 evaluable pts at the lowest dose level; an observed reduction in CD117+ erythroid progenitors in the bone marrow of 1 pt and complete remission with hematologic recovery (CR) in a second pt with primary refractory AML failing 2 lines of induction chemotherapy. The pt with CR later proceeded to HSCT with successful engraftment. Cohort 2 enrollment is ongoing, and further data are forthcoming.

Conclusions: MGTA-117 has been well tolerated with no unexpected safety concerns. Preliminary data show in vivo stability of the ADC with rapid clearance from blood, robust binding of MGTA-117 on CD117+ cells, and early evidence of single-agent biological activity. The observed PK/PD profile in humans is highly consistent with predictions based on data from studies in preclinical species. The trial continues to advance, and progress is being made toward development of MGTA-117 as a myelodepletive conditioning agent for HSCT in AML/MDS and gene therapy indications.

Disclosures: Westervelt: Pfizer: Consultancy. Kebriaei: Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ziopharm: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Artz: Magenta: Honoraria; Abbvie: Honoraria. McCarthy: Magenta Therapeutics: Consultancy, Honoraria; Bluebird Bio: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Axios: Consultancy, Honoraria; Takeda Pharmaceuticals America, Inc.: Consultancy, Honoraria; Partner Therapeutics, Inc.: Consultancy, Honoraria; Karyopharm Therapeutics Inc.: Consultancy, Honoraria; Janssen Global Services, LLC: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy; Genentech: Consultancy, Honoraria; Fate Therapeutics: Consultancy, Honoraria; Starton Therapeutics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein: Auron Therapeutics: Current equity holder in private company; PTC Therapeutics and Syros: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Seattle Genetics, and Biotheryx: Consultancy; Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PinotBio, Bristol Myers Squibb, Jazz Pharmaceuticals, Foghorn Therapeutics, Blueprint Medicines, Gilead Sciences, Janssen Pharmaceuticals: Consultancy; Bayer: Research Funding. Humphrey: Cyteir Therapeutics: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Current Employment. Baeder: Magenta Therapeutics: Current Employment. Lee: Magenta Therapeutics: Current Employment. Occhiuti: Magenta Therapeutics: Current Employment. Tang: Magenta Therapeutics: Current Employment. Santos: Magenta Therapeutics: Current Employment. Bertelsen: Magenta Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company; Janssen Pharmaceuticals: Current equity holder in private company; Abbvie Pharmaceuticals: Current equity holder in private company. Mahender: Magenta Therapeutics: Current Employment. Henry: Magenta Therapeutics: Current Employment. Rose: Magenta Therapeutics: Current Employment.

*signifies non-member of ASH