A phase I study of FHD-286, a dual BRG1/BRM (SMARCA4/SMARCA2) inhibitor, in patients with advanced myeloid malignancies Journal Article


Authors: DiNardo, C. D.; Fathi, A. T.; Kishtagari, A.; Bhalla, K. N.; Quintás-Cardama, A.; Reilly, S. A.; Almon, C.; Patriquin, C.; Nabhan, S.; Healy, K.; Hickman, D.; Collins, M. P.; Khalil, A.; Corrigan, D.; Zhao, T.; Piel, J.; Lyons, K.; Horrigan, K.; Schuck, V.; Martin, P.; Elliott, G.; Lahr, D. L.; Bosinger, M.; D’Aco, K.; Smolen, G. A.; Hentemann, M.; Loghavi, S.; Agresta, S.; Savona, M. R.; Stein, E. M.
Article Title: A phase I study of FHD-286, a dual BRG1/BRM (SMARCA4/SMARCA2) inhibitor, in patients with advanced myeloid malignancies
Abstract: Purpose: Safety and preliminary clinical activity of FHD-286, a dual BRG1/BRM (Brahma related gene 1/Brahma homolog) inhibitor, were evaluated in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Patients and Methods: In this multicenter, open-label, phase I, dose-escalation study (NCT04891757), patients received FHD-286 orally once daily at 2.5, 5, 7.5, and 10 mg. Results: Forty patients (median age: 65.5 years; 85% with adverse genetic status; and 65% with ≥3 prior therapy lines) received FHD-286 for 28 days (median). FHD-286 was not tolerated at 10 mg once daily. Across all doses, treatment-related adverse events (TRAE) were predominantly grade 1 to 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 once daily, respectively. The most common serious TRAE was differentiation syndrome (DS; 10%). An independent committee retrospectively adjudicated DS in 15% of patients (grade 3 in 5 patients and grade 4 in 1 patient). 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. Although antileukemic activity was observed, no objective responses were achieved, and disease progression frequently occurred within 1 to 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. © 2025 American Association for Cancer Research.
Keywords: adult; treatment outcome; aged; aged, 80 and over; middle aged; genetics; leukemia, myeloid, acute; clinical trial; nuclear protein; transcription factor; pathology; transcription factors; nuclear proteins; myelodysplastic syndrome; multicenter study; phase 1 clinical trial; drug therapy; dna helicases; dna helicase; myelodysplastic syndromes; acute myeloid leukemia; very elderly; humans; human; male; female; smarca4 protein, human; smarca2 protein, human
Journal Title: Clinical Cancer Research
Volume: 31
Issue: 12
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2025-06-15
Start Page: 2327
End Page: 2338
Language: English
DOI: 10.1158/1078-0432.ccr-24-3790
PUBMED: 40238563
PROVIDER: scopus
DOI/URL:
Notes: Article -- Source: Scopus
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  1. Eytan Moshe Stein
    362 Stein