Multicenter phase 1 trial of SL-172154 in patients with higher-risk myelodysplastic syndrome or acute myeloid leukemia

SL-172154 is a bispecific CD47 inhibitor and CD40 agonist Fc-fusion protein. A multicenter phase 1 trial evaluated SL-172154 as monotherapy or in combination was azacitidine (AZA) in patients with higher-risk myelodysplastic syndrome (HR-MDS) or acute myeloid leukemia (AML). In the dose escalation part doses of 1, 2, and 6 mg/kg SL-172154 were evaluated as monotherapy or in combination with AZA in patients with relapsed or refractory HR-MDS or AML. In the expansion part the SL-172154 dose that could be safely combined with AZA was evaluated in patients with previously untreated HR-MDS or TP53 mutant (TP53m) AML. Eighty-one patients with HR-MDS (n=33) or AML (n=48) were enrolled in dose escalation (n=37) or expansion (n=44). 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 wildtype) and AML (n=21 with TP53m). CD47 and CD40 engagement by SL172154 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%) AML patients, with median overall survival of 11.0 months (95% CI 5.0-15.6) and 11.7 months (1.97-NE), respectively. Of patients in CR, six of ten HR-MDS and three of six AML patients achieved complete cytogenetic CR. The authors conclude that SL-172154 plus AZA was generally well tolerated with favorable CR rates in patients with TP53m HR-MDS or AML, although without substantial improvement of overall survival compared to historical benchmarks for AZA or AZA-venetoclax, respectively.