A first-in-human study of CD123 NK cell engager SAR443579 in relapsed or refractory acute myeloid leukemia, B-cell acute lymphoblastic leukemia, or high-risk myelodysplasia.

7005 Background: SAR’579 is a trifunctional natural killer (NK) cell engager targeting CD123 antigen and co-engaging NKp46 and CD16a on NK-cells. SAR’579 facilitates the formation of a cytolytic synapse between NK-cells and CD123-positive tumor cells leading to NK-cell activation and tumor cell killing. We herein report preliminary safety and efficacy data of SAR’579 from a phase 1/2 trial in patients with relapsed or refractory acute myeloid leukemia (R/R AML), B-cell acute lymphoblastic leukemia or high risk-myelodysplasia (NCT05086315). Methods: SAR’579 was administered intravenously twice weekly or once weekly (QW), depending on the dose level (DL) for the first 2 weeks of cycle 1 and then weekly for rest of induction cycles. A patient receives approximately three 28-day induction cycles with patients achieving a complete remission (CR) or incomplete hematologic recovery (CRi) per International Working Group criteria transitioning to a 56-day maintenance period with dosing approximately every 29 days. The primary objectives were to establish safety/tolerability and anti-leukemic activity (composite complete remission [CRc] = CR+CRi). Results: With a cutoff date of January 27, 2023, total 23 patients with R/R AML across 6 DLs (3 patients DL1 and 4 each in DL2 - DL6) were included in the safety population. The median age was 70 years (range: 21 - 80) with 9 patients (39.1%) reporting prior hematopoietic stem cell transplantation (HSCT) and 16 (69.6%) had prior exposure to venetoclax. Patients received a median of 2 cycles (range: 1 – 7) for median duration of 7 weeks (range: 1 - 25) and escalating doses of SAR’579 between 10 - 3000 µg/kg/dose in cycle 1 and 100 - 3000 µg/kg QW for the rest of induction cycles. No dose limiting toxicities (DLTs) were observed among the 21 DLT-evaluable patients, until highest dose of 3000 µg/kg QW. The most common treatment emergent adverse events (TEAEs) included infusion-related reactions (n = 10 [43.5%]) and nausea (n = 7 [30.4%]). TEAEs were reported in 22 patients (95.7%) with grade 3/4 adverse events (AEs) in 18 (78.3%) and treatment-related AEs in 16 patients (69.6%), respectively. There were 2 cases of cytokine release syndrome (n = 1 grade 1 and n = 1 grade 2) and no case of immune effector cell-associated neurotoxicity syndrome. No patient reported TEAE leading to permanent discontinuation of SAR’579. The CRc rate was 13.0% (3/23 patients evaluable for response). In DLs with a highest dose of 1000 µg/kg QW, 3/8 (37.5%) patients achieved a CR (2 CR/1 CRi). The median time to first CR/CRi was 16.1 weeks 95% confidence interval (8.1 – Not Estimable [NE]), and the median duration of CR/CRi is NE due to limited follow-up time. Conclusions: SAR’579 was well tolerated up to doses of 3000 µg/kg QW with observed clinical benefit in patients with R/R AML. The trial continues to accrue patients. Clinical trial information: NCT05086315 .