Abstract
Purpose: FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treatment of patients with advanced synovial sarcoma (SS) or SMARCB1-deficient tumors. Patients and methods: In this multinational, open-label, phase 1 study (NCT04965753), patients received FHD609 intravenously at escalating doses either twice weekly (BIW) (5 to 80 mg; n=40) or once weekly (QW) (40 to 120 mg; n=15). Results: Fifty-five patients received FHD-609 for a median of 43 days. The maximum tolerated doses (MTDs) were 40 mg BIW and the equivalent weekly dose, 80 mg QW. Dose-limiting toxicities of QTc prolongation and syncope were observed at 40 and 60 mg BIW. Treatment-related adverse events were predominantly Grade 1-2 in severity, most commonly dysgeusia (40%), dry mouth (29.1%), fatigue (27.3%), and anemia (25.5%). Eleven (20%) patients had treatment-emergent QTcF prolongation preceded by T-wave inversions; 21 (38.2%) patients had T-wave inversions without further cardiac events or ECG abnormalities. FHD-609 showed dose-dependent increases in pharmacokinetic exposure, with no substantial accumulation. Extensive BRD9 degradation in tumor tissue corresponded to downregulation of cancer cell proliferation gene sets. One (2%) patient achieved a partial response; 8 (15%) patients achieved stable disease, which lasted longer than 6 months in 2 patients. Conclusions: FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The MTDs were identified (40 mg BIW/80 mg QW) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.
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