A Phase 1, First-in-Human, Dose-Escalation Study of MGD024, a CD123 x CD3 Bispecific Dart® Molecule, in Patients with Relapsed or Refractory CD123-Positive (+) Hematologic Malignancies

Background

The interleukin-3 receptor alpha chain CD123 is overexpressed in a number of hematologic malignancies and is particularly upregulated in leukemia stem cells, which are believed to serve as a reservoir for relapse (El Achi Cancers 2020). Several investigational agents targeting CD123 with diverse mechanisms of action including bispecific T-cell engagers, antibody-drug conjugates, and Chimeric Antigen Receptor (CAR) T-cell therapies, are being investigated in these malignancies, with many showing preliminary clinical anticancer activity (El Achi Cancers 2020). Of note, the CD123-directed therapy tagraxofusp has now become the standard of care (SoC) for blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Pemmaraju NEJM 2019). MGD024 is an investigational, second-generation CD123 × CD3 DART molecule that can simultaneously bind CD123 on malignant cells and CD3 on T cells, targeting CD123+ leukemic cells for recognition and elimination by CD3+ T lymphocytes as effector cells. MGD024 was engineered to minimize cytokine release syndrome (CRS), while maintaining antitumor activity. This new construct permits intermittent intravenous (IV) dosing due to a longer half-life (Alderson ASH 2021) compared with the first-generation DART molecule flotetuzumab, a continuous-infusion molecule that showed preliminary single-agent activity in refractory acute myeloid leukemia (AML) (Uy Blood 2021). Moreover, preliminary in vitro and in vivo data supported MGD024 clinical investigation as a single agent or in combination with SoC in patients with CD123+ hematologic malignancies (Alderson ASH 2021).

Study Design and Method

This is a Phase 1, first-in-human, dose-escalation study (CP-MGD024-01; NCT05362773) of MGD024 in patients with the following relapsed or refractory hematologic malignancies: AML, myelodysplastic syndrome (MDS), classical Hodgkin's lymphoma (cHL), chronic myeloid leukemia (CML), B-cell acute lymphoid leukemia (B-ALL), hairy cell leukemia (HCL), advanced systemic mastocytosis (ASM), and BPDCN. Eligible patients must have CD123+ malignant cells by flow cytometry or immunohistochemistry, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and no history or current evidence of any condition, therapy, or laboratory abnormality that may confound trial results. Primary objectives are to assess the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) or maximum administered dose (if no MTD is defined) and identify a recommended Phase 2 dose and schedule of MGD024. Secondary objectives include pharmacokinetics, immunogenicity, preliminary assessment of MGD024 clinical activity, and preliminary evaluation of safety/efficacy of tocilizumab in the management of MGD024-induced CRS. Patients receive MGD024 via intermittent intravenous infusion for approximately one year or until discontinuation for unacceptable toxicity or disease progression, whichever occurs first. The dose escalation begins with an accelerated titration phase (1+3 design) and converts to a conventional 3+3 design after the first patient experiences a DLT or a Grade ≥2 nonhematologic adverse event (AE) considered at least possibly related to MGD024 during Cycle 1, whichever occurs first. Safety assessments are based on AEs occurring from the first dose until 30 days after the last dose or until starting another anticancer therapy. Response assessments are performed after Cycle 1, then after every even numbered cycle starting with Cycle 2 until progression or discontinuation, whichever occurs first, and at the end of treatment visit. Response evaluation is determined using modified European LeukemiaNet (ELN) 2017 criteria for ALM and ALL; International Working Group (IWG) 2006 criteria for MDS; Lugano 2014 criteria for cHL; ELN 2020 criteria for CML; 2017 consensus criteria for HCL; IWG-Myeloproliferative Neoplasms Research and Treatment (MRT) & European Competence Network on Mastocytosis (ECNM) 2013 criteria for ASM; and modified criteria from Pemmaraju NEJM 2019 for BPDCN. Patients benefitting from MGD024 may continue to receive MGD024 after completion of the study treatment period, at physician discretion.

Winer:Novartis, Jazz Pharmaceuticals, Pfizer, Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy; Abbvie: Consultancy; Curis: Consultancy. Sharma:Abbvie: Research Funding; Agenus: Research Funding; Alpine: Research Funding; ALX Oncology: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Seven and Eight: Research Funding; Bolt Biotherapeutics: Research Funding; GlaxoSmithKline: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Treadwell: Research Funding; Cullinan: Research Funding; Compugen: Research Funding; Constellation: Research Funding; Coordination: Research Funding; CytomX: Research Funding; Debiopharm: Research Funding; Palleon: Research Funding; eFFECTOR: Research Funding; Genmab: Research Funding; Arrys: Research Funding; Gilead: Research Funding; Helsinn: Research Funding; Innovent: Research Funding; Ikena: Research Funding; InhibRx: Research Funding; Jouce: Research Funding; Kinnate: Research Funding; KSQ: Research Funding; Loxo: Research Funding; Lilly: Research Funding; PureTech: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Alkermes: Research Funding; NGMBio: Research Funding; Onconova: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Repare: Research Funding; Symphogen: Research Funding; Seagen: Research Funding; Servier: Research Funding; KLUS: Research Funding; SK Life Sciences: Research Funding; Shattuck Labs: Research Funding; Biosplice: Research Funding; Sapience: Research Funding; Syros: Research Funding; Epizyme: Research Funding; Odonate: Research Funding; Theratechnologies: Research Funding; Tempest: Research Funding; Tizona: Research Funding; Exelixis: Research Funding; Mersana: Research Funding; Abbvie: Current equity holder in private company; Amgen: Current equity holder in private company; AstraZeneca: Current equity holder in private company; Bristol Myers Squibb: Current equity holder in private company; Gilead: Current equity holder in private company; Johnson & Johnson: Current equity holder in private company; Eli Lilly: Current equity holder in private company; Merck: Current equity holder in private company; Moderna: Current equity holder in private company; Pfizer: Current equity holder in private company; Regeneron: Current equity holder in private company; Vertex: Current equity holder in private company. Kaminker:MacroGenics, Inc.: Current Employment. Zhao:MacroGenics, Inc.: Current Employment; Mallinckrodt Pharmaceuticals: Ended employment in the past 24 months. Ward:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company.