Abstract CT525: GDX012U-001 A phase 1, open-label, dose escalation, and dose expansion study to assess the safety, tolerability, and preliminary antileukemic activity of GDX012 in patients with MRD positive AML
Authors: Knowles Lisa J. , Malik Mohsan , Nussebaumer Oliver , Brown Alice , van Wetering Sandra , Koslowski Michael 
Published: June 2022

Abstract
Background: The presence of minimal residual disease (MRD) in patients that are in complete remission (CR) is associated with an increased risk of relapse and shorter survival in acute myeloid leukemia (AML). Eradication of MRD may improve outcomes for patients with AML; however, to date, therapeutic strategies that target MRD in AML are limited. Vδ1+ γδ T cells are a subset of γδ T cells, that recognize malignant cells through expression of a diverse repertoire of natural cytotoxicity receptors (NCRs) that interact with cognate stress ligands specifically upregulated on diseased cells. Upon target cell recognition, Vδ1+ γδ T cells mediate anti-tumor activity through the direct lysis of transformed cells. The therapeutic potential of human Vδ1+ γδ T cells for the treatment of AML is supported by published preclinical data that show strong and broad antileukemic activity of Vδ1+ γδ T cells in vitro and in vivo (Almeida et al 2016; Di Lorenzo et al 2019). GammaDelta Therapeutics has developed GDX012, a novel allogeneic cell therapy that is enriched for Vδ1+ γδ T cells for the treatment of AML. The cryopreserved drug product is manufactured from a healthy donor leukapheresis that has undergone αβ T cell depletion prior to expansion. GDX012 is a viable (&gt;70% live), pure (CD45 &gt;90%) suspension for IV infusion consisting mainly of Vδ1+ γδ T cells (&gt;60%) expressing a variety of cellular markers that contribute to their function, recognition and targeting of malignant cells. Analysis of the biodistribution of GDX012 in therapeutic murine xenograft models further supports the clinical application of GDX012. When administered systemically, GDX012 shows homing to the bone marrow and is detected for at least 28 days. This suggests that, in addition to high cytotoxic activity against AML blasts, GDX012 also has the capacity to home to and persist in the specific niche where MRD is detected.
Study design: This phase 1, open-label, first-in-human study is comprised of two parts 1) Dose Escalation using 3 + 3 design to sequentially evaluate 4 doses of GDX012; 2) Dose Expansion including at least 10 additional patients at the MTD. The primary objective is to determine safety, tolerability, and the MTD of GDX012. The secondary objective is to evaluate the preliminary antileukemic activity of GDX012 based on detection of MRD in bone marrow. Exploratory objectives will evaluate the kinetics of GDX012 and infiltration in bone marrow and assessment of cytokines in blood and bone marrow. Key eligibility criteria include patients aged ≥18 years of age with histologically confirmed AML who are MRD positive by flow cytometry. Patients must be in first or subsequent CR or CR with incomplete hematological recovery. Eligible patients will undergo lymphodepletion with fludarabine for 4 days and cyclophosphamide for 3 days followed by infusion of GDX012. Patients will be followed for safety for at least 100 days post GDX012 infusion. Antileukemic activity will be evaluated from the bone marrow biopsy at Day 30. Up to 34 patients will be enrolled across 6 US sites. Recruitment to Cohort 1 is ongoing. Clinical trial registry number: NCT05001451
Citation Format: Lisa J. Knowles, Mohsan Malik, Oliver Nussebaumer, Alice Brown, Sandra van Wetering, Michael Koslowski. GDX012U-001 A phase 1, open-label, dose escalation, and dose expansion study to assess the safety, tolerability, and preliminary antileukemic activity of GDX012 in patients with MRD positive AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT525.