A Phase 1 Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients With Advanced Myeloid Malignancies

Purpose: Safety and preliminary clinical activity of FHD-286, a dual BRG1/BRM inhibitor, were evaluated in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Patients and methods: In this multicenter, open-label, phase 1, dose escalation study (NCT04891757), patients received FHD-286 orally once daily (QD) at 2.5, 5, 7.5, and 10 mg. Results: Forty patients (median age 65.5 years; 85% with adverse genetic status; 65% with ≥3 prior therapy lines) received FHD-286 for 28 days (median). FHD-286 was not tolerated at 10 mg QD. Across all doses, treatment-related adverse events (TRAEs) were predominantly Grade 1-2, most commonly dry mouth (27.5%) and increased alanine aminotransferase (20%). Dose-limiting Grade 3 hyperbilirubinemia and Grade 3 muscular weakness occurred at 5 and 10 mg QD, respectively. The most common serious TRAE was differentiation syndrome (DS) (10%). An independent committee retrospectively adjudicated DS in 15% of patients (five Grade 3, one Grade 4). FHD-286 plasma exposure increased with dose and accumulated with continuous dosing. Exposures were typically higher with concomitant CYP3A4 inhibitors. Myeloid differentiation and leukemic burden reduction were observed across cytogenetic and mutational backgrounds, notably in patients with enhancer-driven genotypes. There were no objective responses. Conclusions: DS was the most frequent serious TRAE. While antileukemic activity was observed, no objective responses were achieved and disease progression frequently occurred within 1-2 treatment cycles. Blast reductions were reported across cytogenetic and mutational profiles, coupled with myeloid differentiation via BRG1/BRM inhibition. This novel mechanism warrants further investigation of FHD-286 in combination with other agents in myeloid malignancies.