Phase 1 dose escalation and expansion trial of the bispecific CD47 inhibitor and CD40 agonist Fc-fusion protein SL-172154 (SIRPα-Fc-CD40L) in patients with higher-risk myelodysplastic syndrome or acute myeloid leukemia.

Abstract

This clinical trial sought to determine whether SL-172154 could be combined safely and improve the efficacy of azacitidine (AZA) in patients with higher-risk myelodysplastic syndrome (HR-MDS) or acute myeloid leukemia (AML). Dose escalation: doses of 1, 3, and 6 mg/kg SL-172154 was evaluated as monotherapy or in combination with AZA in patients with relapsed, refractory HR-MDS or AML. Expansion: a SL-172154 dose that could be safely combined with AZA was evaluated in patients with previously untreated HR-MDS or TP53 mutant (TP53m) AML. safety, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity. Eighty-one patients with HR-MDS (n = 33) or AML (n = 48) were enrolled in dose escalation (n = 37) or expansion (n = 44). Infusion-related reaction was the most common SL-172154-related toxicity and led to a dose limiting toxicity at 6 mg/kg. A dose of 3 mg/kg SL-172154 plus AZA was evaluated in patients with previously untreated HR-MDS (n = 21 with TP53m and n = 3 with TP53 wild type) and AML (n = 21 with TP53m). CD47 and CD40 engagement by SL-172154 was detected on leukemic blasts, myeloid, and lymphoid cells. Complete remission (CR) was achieved in 10 of 24 (43%) HR-MDS and six of 21 (29%) TP53m AML patients with median overall survival (OS) of 11.0 months (95% CI, 5.0-15.6) and 11.7 months (95% CI, 1.97-NE), respectively. Of patients in a CR, six of 10 HR-MDS and three of six TP53m AML patients achieved complete cytogenetic CR. SL-172154 plus AZA was generally well tolerated with favorable CR rates in pts with TP53m HR-MDS or AML, although without substantial improvement in OS when compared to historical benchmarks for AZA or AZA/VEN, respectively.