An Open-Label, First-in-Human, Dose-Escalation Study of SAR443579 Administered As Single Agent By Intravenous Infusion in Patients with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML), B-Cell Acute Lymphoblastic Leukemia (B-ALL) or High-Risk Myelodysplasia (HR-MDS)

Background: SAR443579 is a trifunctional Natural Killer Cell Engager (NKCE) targeting the CD123 tumor antigen on cancer cells and co-engaging NKp46 and CD16a on NK cells. SAR443579 is designed as an NKCE to facilitate the formation of a cytolytic synapse between NK cells and CD123-positive tumor cells leading to NK cell activation via its binding to NKp46 and CD16a resulting in tumor cell killing. Preclinical studies demonstrated SAR443579 enabled potent antitumor activity against primary AML blasts and AML cell lines, promoted strong NK cell activation and induced cytokine secretion only in the presence of AML target cells. In vivo studies demonstrated strong overall survival in an aggressive human AML xenograft model. Treatment of non-human primates with SAR443579 resulted in sustained depletion of circulating CD123+ cells that was well tolerated with no adverse clinical signs and only minimal induction of pro-inflammatory cytokines as compared to a T cell engager approach targeting CD123, up to a dose of 3 mg/kg.

Study Design and Methods: This is an open-label, multi-center, first-in-human study to evaluate the safety and clinical benefit of SAR443579 as a monotherapy for the treatment of patients with R/R AML, B-ALL and HR-MDS. The trial will be performed in two parts, an initial dose escalation followed by dose expansion. The escalation part aims to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of SAR443579 based on the occurrence of dose limiting toxicities (DLTs) in the first 28-day cycle. Dose escalation will proceed using a Bayesian logistic regression model with approximately 42 participants. SAR443579 treatment consists of an Induction Phase with three 28-day cycles, followed by a Maintenance Phase of up to thirteen 56-day cycles. Depending on the dose level, SAR443579 will be administered twice weekly (Q2W) or once weekly (Q1W) in the first 1 or 2 weeks of Cycle 1 and Q1W during the last 2 weeks of Cycle 1. For all subsequent induction cycles, dosing will be Q1W. Key inclusion criteria for the escalation are age ≥12 years, R/R AML, CD123+ R/R B-ALL and CD123+ HR-MDS that have no available (or are ineligible for) therapy with known clinical benefit.

Key exclusion criteria are Eastern Cooperative Oncology Group (ECOG) performance status (≥18 years-old) >2, Karnovsky Scale (16-17 years-old) <50% or Lansky Scale (<16 years-old) <50%. Patients with active central nervous system leukemia at the time of enrollment are excluded. Prior hematopoietic stem cell transplantation (HSCT) with relapse beyond 3 months may be included only if off immunosuppression for a minimum of 4 weeks and no evidence of graft versus host disease (GVHD). Patients with white blood cell count ≥15000/mm³ are excluded and use of hydroxyurea should be discontinued at least 1 day before first planned IMP administration.

TCD17197 will enroll approximately 82 participants over the dose escalation and expansion phases. Participants with R/R AML, B-ALL and HR-MDS will be enrolled in the dose escalation phase to identify the preliminary RP2D. During the expansion phase, participants with R/R AML will be enrolled into 2 cohorts concurrently. Cohort A will include participants meeting inclusion criteria for primary induction failure or early relapse AML (occurring 6 months or less after an initial remission on prior induction treatment). Participants in Cohort B will meet inclusion criteria for AML patients and have had late relapse, occurring more than 6 months after an initial remission on prior induction treatment.

SAR443579 is administered intravenously over 1 hour. Participants receive induction cycles (28 days/cycle) until achieving complete remission or progressive disease. Participants in complete remission who are unable to undergo HSCT, for any reason, are eligible to receive SAR443579 maintenance dosing, up to 13 cycles.

The primary study objective is to determine the MTD or MAD of SAR443579 as a single agent (dose escalation) and to assess the anti-leukemic activity at the RP2D in participants with R/R AML (dose expansion). Secondary objectives include characterization of the overall safety and tolerability profile, PK profile, immunogenicity, alternative indicators of antitumor activity, and rate of HSCT. This study will be conducted in Australia, France, the Netherlands, and the United States. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT05086315

Stein:Amgen: Speakers Bureau. Bajel:Abbvie: Honoraria; Amgen: Honoraria, Speakers Bureau; Astellas: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria. Fleming:AbbVie: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Jongen-Lavrencic:Ellipses Pharma: Research Funding. Garciaz:Amgen: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Abbvie: Honoraria; Servier: Consultancy, Honoraria. Boissel:GILEAD: Honoraria; AMGEN: Honoraria; ARIAD/INCYTE: Honoraria; ASTELLAS: Honoraria; NOVARTIS: Honoraria; SERVIER: Honoraria. De Botton:Daiichi Sankyo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Forma Therapuetics: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria; Bayer: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Pierre Fabre: Consultancy; Janssen: Consultancy, Honoraria. de Leeuw:Roche: Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avigan:Takeda: Consultancy; Parexel: Consultancy; Janssen: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Legend Bio Tech: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd.: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Partners Tx: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kite: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Kite: Consultancy; Sanofi: Consultancy; Kowa: Consultancy. Jensen:Sanofi: Current Employment, Current equity holder in publicly-traded company. Demers:Sanofi: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Wagenaar:Sanofi: Current Employment, Current equity holder in private company. Mi:Sanofi: Current Employment, Current equity holder in publicly-traded company. Ziti-Ljajic:Sanofi: Current Employment. Draganov:Sanofi: Current Employment, Current equity holder in publicly-traded company. Abbadessa:Sanofi: Current Employment, Current equity holder in publicly-traded company. Wei:Walter and Eliza Hall Institute of Medical Research: Current Employment, Other: receives milestone and royalty payments related to venetoclax; Astellas: Consultancy; Abbvie: Consultancy, Research Funding; Servier: Consultancy, Research Funding.