A Phase I, Single-Arm, Open Label, Dose Escalation, Multicenter Study of Off-the-Shelf Natural Killer (NK) Cells (SAR445419) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)

Background and Significance: SAR445419 (SAR'419) is an allogeneic, off-the-shelf, donor-derived, natural killer (NK) cell investigational immunotherapy. NK cells in SAR'419 are expanded ex vivo using PM21 particles expressing membrane-bound interleukin-21 and 4-1BB ligand from the plasma membranes of feeder cells (Ciurea et al, Leukemia, 2022). Ex vivo, PM21 expansion allows for large numbers of hyperactive NK cells to be generated and administered, thereby increasing therapeutic potential to patients. It is hypothesized that mature, fully functional NK cells expanded ex vivo will have superior anti-tumor activity, favorable safety profile, and can induce remissions, enabling patients to receive curative allogeneic hematopoietic stem cell transplantation (HSCT), thereby improving outcomes in patients with R/R AML. Two phase 1/2 dose-escalation and expansion studies (NCT01787474, NCT02809092) of ex vivo expanded haploidentical donor NK cells infused as 6 doses over a course of 2 weeks, after fludarabine and cytarabine chemotherapy, demonstrated this approach to be feasible with favorable safety profile in patients with R/R AML. This study aims to determine the candidate dose(s), evaluate safety, tolerability, and preliminary anti-tumor activity of SAR'419 administered after fludarabine and cytarabine chemotherapy for adult patients with R/R AML.

Study Design and Methods: This is a phase 1, single-arm, dose escalation study (NCT05712278). The primary objective is to determine the candidate dose(s) based on the evaluation of dose-limiting toxicities (DLTs). The DLT evaluation period is from start of chemotherapy (Day -6) until 28 days after the first administration of SAR'419, starting at the lowest dose. Eligible patients will be administered fludarabine, 30 mg/m ²/day and cytarabine, 2 g/m ²/day (Day -6 to Day -2) for 5 days followed by 6 doses of SAR'419 (intravenous) given thrice weekly over 2 weeks beginning on Day 1. Approximately 12 DLT-evaluable patients will be enrolled. The treatment period will start from the first administration of chemotherapy (Day -6) until end of treatment on Day 56, and subsequently patients will have follow-up visits every 2 months. Dose escalation will be guided by the modified toxicity probability interval 2 design. Key secondary objectives include characterization of overall safety, tolerability, HSCT rate, impact of SAR'419 on infection, and preliminary anti-leukemic activity of SAR'419 (as per international working group criteria). Biomarkers in whole blood (including serum and plasma) and bone marrow (aspirates-liquid, and biopsy-solid) will be evaluated to assess the impact of SAR'419 treatment.

Key inclusion criteria are adult participants with confirmed diagnosis of R/R AML according to World Health Organization classification, including participants with relapsed AML in the bone marrow after allogeneic HSCT (including those who have received donor lymphocyte infusions); with or without concomitant or with isolated central nervous system or extramedullary disease who have received at least 1 prior line of therapy for AML. Key exclusion criteria are participants with a second primary malignancy requiring active therapy (adjuvant hormonal therapy is allowed); with known acquired immunodeficiency syndrome or human immunodeficiency virus disease requiring antiretroviral treatment or having active hepatitis B or C infection, or symptomatic severe acute respiratory syndrome coronavirus 2 infection; and who are receiving >10 mg/day of oral prednisone or equivalent.

In the safety analyses, all DLT modeling will be performed on the DLT-evaluable population or those who experienced a DLT. All other safety analyses will be performed on the safety population using descriptive statistics.

This study is actively recruiting at this time and is being conducted in the United States.