Background: CD47 blocking antibodies and SIRPα-Fc fusion proteins have demonstrated activity in combination with azacitidine (AZA) in previously untreated (UnTx) HR-MDS and AML pts. SL-172154 (SIRPα-Fc-CD40L), a hexameric, bi-functional fusion protein consisting of SIRPα domains linked to CD40L domains through an inert Fc linker demonstrated improved anti-tumor activity in comparison to naked CD47 blocking antibodies in pre-clinical studies [de Silva et al. Cancer Immunol Res 2020]. SL-172154, as a CD47 inhibitor, requires combination with AZA to enhance pro-phagocytic signals on leukemic stem cells/blasts thereby potentiating macrophage phagocytosis in AML/HR-MDS. Here we report the results from the Phase 1 Dose Escalation. cohorts for SL-172154 monotherapy [SL-mono] and for SL-172154 + AZA combination [SL-AZA] in pts with HR-MDS or AML.

Methods: The objectives of the dose escalation cohorts include evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic effects and efficacy per IWG 2006 for MDS and ELN 2017 for AML. SL-172154 was administered IV weekly of a 28-day cycle as monotherapy or with AZA 75 mg/m 2 for 7 days per cycle. mTPI-2 was used for dose escalation with a DLT threshold of 20%. Pts ≥ 18 years old with R/R HR-MDS or R/R AML were eligible for dose escalation cohorts. In addition, UnTx pts with TP53 mutant (TP53m)-MDS were eligible for SL-AZA cohorts.

Results: As of May 25, 2023, 37 pts were enrolled (19 in SL-mono; 18 in SL-AZA cohorts): 14 women; median age 70 years [range 44-81]. 27 pts had R/R AML (16 de novo; 11 secondary), 5 had R/R MDS, and 5 were UnTx TP53m-MDS. 23 (85%) of 27 R/R AML pts had adverse genetic abnormalities per 2017 ELN classification, including 9 (33%) with TP53m or del 17. The median number of prior lines of AML therapy was 2 [range 1-4]; 25 (93%) had received venetoclax (VEN) and 23 (85%) had received a hypomethylating agent (HMA). All 5 pts with R/R MDS had previously received HMA and 2 pts were previously treated with VEN. SL-172154 was dose escalated as monotherapy or with AZA as shown in Table 1. Infusion-related reactions (IRRs) were the most common SL-172154-related treatment-emergent AEs (TEAEs) reported in 13 (68%) and 8 (44%) pts in SL-mono and SL-AZA cohorts, respectively. IRRs (51 events) were Grade (G) 1 or 2 except for 3 G3 events (1 each at 6 mg/kg SL-mono and SL-AZA; 1 at 3 mg/kg SL-mono). Other SL-172154-related TEAEs observed in ≥ 3 pts were AST increased (4; 21%), ALT increased (3; 16%) and nausea (3; 17%) in SL-mono cohorts, and nausea (3; 17%) in SL-AZA cohorts. All events of AST/ALT increased were transient. Only one DLT (G3 IRR in the 6 mg/kg SL-AZA cohort) was reported, which required a dose reduction to 3 mg/kg.

As of July 10, 2023, in SL-mono cohorts, 1 pt with R/R AML post 7+3, FLAG and VEN/AZA achieved Morphologic Leukemia-Free State (blast reduction from 19% to <5%) after 1 cycle of 6 mg/kg SL-172154 and proceeded to allogeneic hematopoietic cell transplant (allo-HCT) after cycle 2. In 12 evaluable pts with R/R AML receiving SL-AZA, although no objective responses (OR) were observed, relative reduction in bone marrow (BM) blasts from baseline was reported in 2/5 pts at 1 mg SL-AZA (-50%, -75%) and 5/7 pts at 3 mg SL-AZA (ranging from -35% to -90%). One pt underwent an allo-HCT. In 4 evaluable pts with UnTx TP53m-MDS, the ORs were 1 complete remission (CR), 1 marrow CR, and 2 stable disease. 2 of them proceeded to allo-HCT.

SL-172154 induced elevations in serum IL-12p40, IP-10, IL-8, IL-10, MIP3α and MCP1: greater response at 3 mg/kg compared to 1 mg/kg while similar between 3 and 6 mg/kg. In the BM, SL-172154 induced a dose-dependent increase in phagocytic cells (CD11b, HLA-DR, CD16, CD36 and CD64) within mature myeloid immune cell compartments (CD45highCD34-). Reduction in leukemic blasts (CD45lowCD34+) was associated with an increase in mature myeloid and phagocytic cell phenotypes (3 mg/kg SL-AZA > 1 mg/kg SL-AZA).

Conclusions: SL-172154 was well tolerated up to 3 mg/kg as monotherapy and in combination with AZA. Preliminary efficacy signals were detected in UnTx TP53m-MDS and R/R AML. A response to SL-172154 monotherapy, dose-dependent increases in serum cytokines and accumulation of mature myeloid cells in BM suggest a potential role for CD40 stimulation. Based on the safety, preliminary efficacy and pharmacodynamic activity, 3 mg/kg SL-172154+ AZA is being evaluated in treatment naïve pts with TP53m AML and HR-MDS.

Daver:Novartis: Consultancy; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Hanmi: Research Funding; Gilead: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Shattuck Labs: Consultancy; Agios: Consultancy; FATE: Research Funding; Astellas: Consultancy, Research Funding; Kronos Bio: Research Funding; Servier: Consultancy, Research Funding; Jazz: Consultancy; Syndax: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; AROG: Consultancy; Novimmune: Research Funding; Trovagene: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy. Stein:Amgen: Speakers Bureau. Chai-Ho:Syros: Research Funding; Sun Pharma: Research Funding; Gilead: Research Funding; Shattuck Labs: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding. Zeidner:Stemline: Research Funding; Takeda: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Novartis: Consultancy; Merck: Research Funding; Sellas: Consultancy; Servier: Consultancy, Honoraria; Shattuck Labs: Honoraria, Research Funding; Arog: Research Funding; Jazz: Research Funding; Astex: Research Funding; Daiichi Sankyo: Honoraria; Immunogen: Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Foghorn: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding. Maher:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Sobi (Doptelet): Speakers Bureau. Stahl:Clinical care options: Other: GME activity ; Rigel: Membership on an entity's Board of Directors or advisory committees; Boston Consulting: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: GME activity ; Haymarket Media: Other: GME activity ; Curis Oncology: Other: GME activity ; Dedham group: Consultancy; Kymera: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Yee:Astex, Forma Therapeutics, F. Hoffmann-La Roche, Genentech, Geron, Gilead Sciences, Janssen, Jazz, Novartis, Treadwell Therapeutics: Research Funding; AbbVie, Novartis, Taiho: Honoraria; Bristol Myers Squibb/Celgene, F. Hoffmann-La Roche, GSK, Jazz, Novartis, Pfizer, Shattuck Labs, Taiho Oncology, Takeda: Membership on an entity's Board of Directors or advisory committees. Curran:Kite: Other: Advisory board; Amgen: Other: Advisory board; Servier: Consultancy, Other: Expert consensus panel; Jazz: Other: Advisory board; Pfizer: Honoraria, Other: Advisory board; Incyte: Other: Advisory board. Ito:BlueSphere Bio: Patents & Royalties: Patent , Research Funding; Horizon Therapeutics: Other: Clinical trial drug supply . Sochacki:Abbvie: Other: Research and or clinical trial support; Shattuck labs: Other: Research and or clinical trial support; ALX oncology: Other: Research and or clinical trial support; Boehringer Ingelheim: Other: Research and or clinical trial support; Macrogenics: Other: Research and or clinical trial support; Regeneron: Other: Research and or clinical trial support; Incyte: Other: Research and or clinical trial support. Sallman:AbbVie, Affimed Gmbh, Gilead, Incyte, Intellisphere, LLC, Molecular Partners AG, PGEN Therapeutics, Inc., Takeda, Zentalis; Advisory board for AvenCell, BlueBird Bio, BMS, Intellia, Jasper Therapeutics, Kite, Magenta Therapeutics, NKARTA, Novartis, Orbita: Consultancy; Aprea, Jazz: Research Funding. Hernandez:Shattuck Labs: Current Employment. Metenou:Shattuck Labs: Current Employment; Precigen: Current equity holder in publicly-traded company; Compass therapeutics: Current equity holder in publicly-traded company. Ma:Shattuck Labs: Current Employment; GlaxoSmithKline: Current equity holder in publicly-traded company. Kato:Shattuck Labs: Current Employment; Bristol Myers Squibb: Current equity holder in publicly-traded company. Zeidan:Boehringer-Ingelheim: Consultancy, Honoraria; Astex: Research Funding; Agios: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; Lox Oncology: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Foran: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Notable: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Shattuck Labs: Research Funding; Kura: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Schrödinger: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria.

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2023
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