TIP: A phase I/II study of MGTA-117, an anti-CD117 antibody-drug conjugate, in patients with adult acute myeloid leukemia (AML) and myelodysplasia with excess blasts (MDS-EB).

TPS3156 Background: Hematopoietic stem cell transplantation (HSCT) is used with curative intent for AML and MDS-EB. MGTA-117 is a novel Ab-drug conjugate (ADC) in development for conditioning prior to HSCT. MGTA-117 selectively targets CD117 (c-Kit) with a human monoclonal Ab to CD117 conjugated to an amanitin payload that depletes CD117-expressing cells by inhibiting RNA polymerase II. Human hematopoietic stem cells and AML tumor cells express high levels of CD117, and MGTA-117 potently depletes these target cells, with an IC50 of <10pM in vitro. MGTA-117 has demonstrated in vitro and in vivo stability, confirming its characterization as a highly potent and selective agent. In a primate GLP toxicology study, MGTA-117 maximally depleted bone marrow stem cells at a dose not associated with evidence of toxicity in other tissues. Dose-dependent reduction of peripheral reticulocytes, produced from CD117+ erythroid precursors in the bone marrow, was an early and time sensitive biomarker of bone marrow CD117+ cell depletion. Higher doses were associated with the elevation of transaminases and histopathology that were asymptomatic and transient. Highest Non- Severely Toxic Dose (HNSTD) was used to establish the starting dose in this First-in-Human study. Based upon dose exposure and allometric scaling, it is expected that the clinical exposures after a 0.02 mg/kg dose in the first human cohort will provide an optimal > 100-fold safety margin over exposures observed after the 0.3 mg/kg dose that was the HNSTD in the primate GLP toxicology study. Methods: This phase I/II, multicenter, open-label, dose-escalation study will investigate the safety, tolerability, PK profile, PD activity, and blast depletion activity of MGTA 117 given intravenously as a single dose in adults with R/R AML or MDS-EB. Patients must be 18-75 yrs, have a WHO-defined diagnosis of CD117+ R/R AML or MDS-EB with ≥5% marrow myeloblasts. Patients must have ECOG PS ≤2, and adequate hepatic, renal, and cardiac function. The primary objective is to establish a minimum safe and biologically effective (MSBE) dose of MGTA-117 in R/R AML and MDS-EB patients based on safety and CD117 receptor occupancy (RO) in circulating leukemic blasts after dosing. The observation period for dose limiting toxicities is 21 days. Patients will be followed for changes in reticulocyte, neutrophil, and platelet counts in PB and percent change from baseline in leukemic blasts or stem/progenitor cells in PB and/or BM. CD117 receptor occupancy by MGTA-117 will be measured and MSBE dose will be based on safety and receptor occupancy. The study is designed with the possibility that subjects would proceed to HSCT >28 days after MGTA-117 administration, if eligible per the local transplant practices. Clinical trial information: NCT05223699.