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

Background 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). Methods 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 ( TP53 m) AML. Objectives: safety, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity. Results 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 TP53 m and n = 3 with TP53 wild type) and AML ( n = 21 with TP53 m). 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%) TP53 m 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 TP53 m AML patients achieved complete cytogenetic CR. Conclusions SL‐172154 plus AZA was generally well tolerated with favorable CR rates in pts with TP53 m HR‐MDS or AML, although without substantial improvement in OS when compared to historical benchmarks for AZA or AZA/VEN, respectively.