Phase 1/2, Open-Label, Multi-Center Study Assessing the Safety, Tolerability and Preliminary Efficacy of CD123 Natural Killer Cell Engager (NKCE), SAR443579, in Combination with Venetoclax and Azacitidine in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Who Are Ineligible for Intensive Chemotherapy

Background and Significance:

SAR443579 (SAR'579) is an NKCE composed of three distinct binding domains designed to co-engage CD123 on tumor cells and the activating receptors NKp46 and CD16a on natural killer (NK) cells. CD123 is highly expressed on leukemic blasts and is associated with poor outcomes in various hematologic malignancies. This offers a potential target for AML treatment.

Patients (pts) with AML have poor long-term survival and high rates of relapse and resistance. First-line treatment of AML consists primarily of intensive chemotherapy (IC) and is often combined with a targeted therapy. Venetoclax in combination with azacitidine (VEN/AZA) is the established standard of care for pts with newly diagnosed AML (ND-AML) who are older or unfit for IC. VEN/AZA has improved response rates in these pts, however durability of response after targeted therapy could be much improved upon.

NKCEs are designed to harness the antitumor killing activity of NK cells by engaging both activating receptors on NK cells and tumor-specific antigens. SAR'579 promotes NK-cell activation and tumor cell death by forming a cytolytic synapse between NK cells and CD123-positive leukemic cells, while minimizing the potential for off-target activation. In preclinical studies, a CD123-NKCE demonstrated strong antitumor activity against AML cell lines in vitro and reduced the number of CD123-positive cells ex vivo when exposed to AML blasts. Early clinical results in relapsed/refractory AML pts demonstrated that SAR'579 had a manageable toxicity profile up to 6.0 mg/kg/infusion, and complete remissions (CRs) were identified at a target dose of 1.0 mg/kg/infusion. SAR'579 received Fast Track designation by the US FDA.

Here, we describe the design of sub-study 1 which is a Phase 1/2 trial to assess the safety, tolerability, and preliminary efficacy of SAR'579 in combination with VEN/AZA in pts with ND-AML who are ineligible for IC.

Study Design and Methods:

The study (NCT06508489) is structured with individual sub-studies that will explore SAR443579 with combination partners, which may include approved or investigational agents. In this sub-study 1, eligible pts aged ≥18 years with a confirmed diagnosis of CD123 expressing AML who are ineligible for IC will receive SAR443579, in combination with VEN/AZA. Pts ≥75 years must have an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 and patients 18-74 years must have an ECOG PS ≤3. The exclusion criteria includes a diagnosis of acute promyelocytic leukemia, active central nervous system involvement with AML at enrollment, cardiovascular disease of Class ≥2, malabsorption syndrome, and a baseline QTc interval exceeding 470 msec. Pts will also be excluded if they have received at least one of the following: previous treatment with venetoclax, chemotherapeutic or hypomethylating agents, or other experimental therapies for AML; and those who have received strong or moderate CYP3A inducers 7 days prior to the initiation of study treatment.

Intravenous (IV) SAR'579 is to be administered weekly for induction and every 4 weeks for maintenance in combination with oral venetoclax and IV or subcutaneous azacitidine at the recommended doses. The duration of each cycle will be 28 days. Pts will start induction treatment and switch to maintenance/continued therapy after achieving response. They will receive treatment until disease progression, treatment discontinuation, unacceptable adverse events (AEs) or maximum number of treatment cycles permitted.

Primary endpoints will determine the preliminary recommended dose(s) for optimization of SAR'579 by measuring the incidence of dose-limiting toxicities in Part 1 (dose escalation), the recommended dose for expansion of SAR'579 by assessing overall safety and preliminary anti-tumor activity in Part 2 (optimization) and will assess the CR rate in Part 3 (expansion).

Secondary endpoints will assess safety and tolerability (treatment-emergent AEs, serious AEs, AEs of special interest, and laboratory abnormalities), incidence of anti-drug antibodies, percentage of pts with minimal residual disease, pharmacokinetics, immunogenicity and additional parameters of anticancer activity.

For Part 1, an estimated 9-18 pts will be enrolled. The expected duration of this sub-study 1 is approximately 5 years with a follow-up period of 2 years post-treatment. The study is currently recruiting.

Funding: Sanofi

Stein:Syndex Bio: Consultancy, Honoraria; Debio Pharma: Consultancy, Honoraria; Sanofi and Daiichi Sankyo: Consultancy; Amgen: Honoraria, Speakers Bureau. Searle:Shattuck Labs, Sanofi, BMS, DarkBlue Therapeutics: Consultancy; Janssen, Abbvie, Beigene, BMS, Nurix: Honoraria; Pfizer, Janssen, Jazz, Abbvie: Speakers Bureau. Garciaz:Janssen: Consultancy, Honoraria; Imcheck Therapeutics: Consultancy; Servier: Consultancy, Honoraria; Sanofi: Consultancy, Other: travel grant; Abbvie: Consultancy, Honoraria, Other: Travel grant; BMS: Consultancy. Borate:Daiichi Sankyo: Consultancy; Takeda: Other: IDMC; BMS: Consultancy; Genentech: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Ryvue: Other: IDMC; Rigel: Consultancy; Astellas: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Sumitomo: Consultancy. Jensen:Sanofi: Current Employment. Kefsi:Sanofi: Current Employment. Bernardo:Sanofi: Current Employment. Yang:Sanofi: Current Employment. Cooley:Sanofi: Current Employment. Bajel:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Glaxo-Smith-Kline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria.