First-in-Human Study of the CD123 NK Cell Engager SAR443579 in Relapsed or Refractory Acute Myeloid Leukemia, B-Cell Acute Lymphoblastic Leukemia or High Risk-Myelodysplasia: Updated Safety, Efficacy, Pharmacokinetics and Pharmacodynamics
Authors: Bajel Ashish , Garciaz Sylvain , Desai Pinkal , Huls Gerwin A , Maiti Abhishek , Jongen-Lavrencic Mojca , Boissel Nicolas , De Botton Stephane , de Leeuw David C. , Fleming Shaun , Zwaan C. Michel , Arellano Martha , Avigan David , Saultz Jennifer N. , Mantzaris Ioannis , Jensen Kyle , Wagenaar Timothy , Mi Gu , Ziti-Ljajic Samira , Draganov Dobrin , Abbadessa Giovanni , Stein Anthony Selwyn 
Published: December 2023

Introduction: SAR443579 (SAR'579) is a trifunctional anti-CD123 NKp46xCD16 natural killer cell engager, facilitating the formation of a cytolytic synapse between natural killer (NK)-cells and CD123-positive tumor cells leading to NK-cell activation and tumor cell killing. Herein, we report data of SAR'579 from TCD17197, an on-going phase 1/2 trial in patients (pts) with relapsed or refractory acute myeloid leukemia (R/R AML), B-cell acute lymphoblastic leukemia or high risk-myelodysplasia (HR-MDS) (NCT05086315).
Methods: TCD17197 is a first-in human, open-label, multicenter study designed to characterize the overall safety and tolerability profile of SAR'579 and to assess preliminary anti-leukemic activity per International Working Group criteria. SAR'579 was administered intravenously for three 28-day induction cycles, either twice weekly or once weekly (QW), depending on the dose level (DL) for the first 2 weeks and then weekly for the remainder of the induction cycles. Pts achieving a complete remission (CR) or incomplete hematologic recovery (CRi) transitioned to maintenance with dosing approximately once every four weeks. Bone marrow and peripheral blood samples were taken at various time points to assess treatment response, pharmacokinetics, and pharmacodynamics.
Results: As of July 05, 2023, 43 pts (42 R/R AML and 1 HR-MDS) across 8 DLs at 10 - 6000 µg/kg/dose (3 in DL1, 4 each in DL2 - DL5 and 8 each in DL6 - DL7 and DL1mg) were included. The median age was 68 years (21 - 81). Pts had received a median of 2.0 (1.0 -10.0) prior lines of treatment with 13 pts (30.2%) reporting prior hematopoietic stem cell transplantation and 36 pts (83.7%) withprior exposure to venetoclax. Median white blood cell count at screening was 2.8 × 10 9/L (0.2 - 12.2 × 10 9/L). Median bone marrow blast burden at study entry was 50% (2.8 - 90.0) and 7 (16.28%) pts had extramedullary disease. Pts received a median of 2 cycles (1 - 9) with a median treatment duration of 7.9 weeks (1 - 49). No dose limiting toxicities (DLTs) were observed up to the highest dose of 6000 µg/kg QW. TEAEs were reported in 42 pts (97.7%) with grade ≥3 adverse events (AEs) in 28 pts (65.1%). No TEAE lead to the permanent discontinuation of SAR'579. The most common treatment-emergent adverse events (TEAEs) were infusion-related reactions (n = 29 [67.4%]) and constipation (n = 11 [25.6%]) all being ≤ grade 2 events. Treatment-related AEs occurred in 32 pts (74.4%), with one (2.3%) grade 4 neutropenia. There were 2 cases of grade 1 cytokine release syndrome at DL4 and DL5, and no case of immune effector cell-associated neurotoxicity syndrome. The composite complete remission rate (CR+CRi) was 12.0% (5/42 R/R AML). In DLs with a highest dose of 1000 µg/kg QW, (DL3, DL4, DL1mg) 5/15 (33.3%) pts achieved a CR (4 CR/1 CRi) as of the cut-off date. Complete remissions were observed upon completion of 1 (CR & CRi), 2, 3 and 4 cycles of treatment, and the median duration of CR/CRi is not estimable. Data from updated PK/PD and in vitro mechanistic analyses studying dose-response relations will be presented.
Conclusions: SAR'579 was well tolerated up to doses of 6000 µg/kg QW with observed clinical benefit in pts with R/R AML. The results are consistent with the predicted favorable safety profile.