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4278 Safety, Pharmacodynamic, and Anti-Tumor Activity of SL-172154 As Monotherapy and in Combination with Azacitidine (AZA) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) Patients (pts)

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III
Hematology Disease Topics & Pathways:
Biological therapies, Checkpoint Inhibitor, drug development, Therapies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Naval Daver, MD1, Anthony Selwyn Stein, MD2, Dale Bixby, MD, PhD3*, Wanxing Chai-Ho, MD4, Joshua F. Zeidner, MD5, Keri Maher, DO6, Don A. Stevens, MD7, Maximilian Stahl, MD8, Karen Yee, MD9*, Emily K Curran, MD10, Sawa Ito, MD11, Andrew Sochacki, MD12, David A Sallman, MD13, Robert Hernandez, PhD14*, Simon Metenou, PhD14*, Bo Ma, PhD14*, Kazunobu Kato, MD15 and Amer M. Zeidan, MBBS, MHS16

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2City of Hope National Medical Center, Duarte, CA
3University of Michigan Health Systems, Ann Arbor, MI
4Department of Medicine/Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA
5University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC
6Massey Cancer Center, Virginia Commonwealth University, Richmond, VA
7Norton Cancer Institute St. Mathew's, Louisville, KY
8Dana Farber Institute, Boston, MA
9Princess Margaret Cancer Center (PMCC), Toronto, ON, CAN
10University of Cincinnati, Cincinnati, OH
11Hematology and Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
12START Midwest, Grand Rapids, MI
13H. Lee Moffitt Cancer Center, Tampa, FL
14Shattuck Labs, Durham, NC
15Shattuck Labs, Raleigh, NC
16Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, Yale University, New Haven, CT

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/m2 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.

Disclosures: 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: GSK: Membership on an entity's Board of Directors or advisory committees; Boston Consulting: Consultancy; Kymera: Membership on an entity's Board of Directors or advisory committees; Dedham group: Consultancy; Rigel: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: GME activity ; Clinical care options: Other: GME activity ; Haymarket Media: Other: GME activity ; Curis Oncology: Other: GME activity . 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.

*signifies non-member of ASH