A Phase I Study of FHD-609, a Heterobifunctional Degrader of Bromodomain-Containing Protein 9, in Patients with Advanced Synovial Sarcoma or SMARCB1-Deficient Tumors

Purpose: FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treating patients with advanced synovial sarcoma or SMARCB1-deficient tumors. Patients and Methods: In this multinational, open-label, phase I study (NCT04965753), patients received FHD-609 intravenously at escalating doses either twice weekly (5–80 mg; n ¼ 40) or once weekly (40–120 mg; n ¼ 15). Results: Fifty-five patients received FHD-609 for a median of 43 days. The maximum tolerated doses were 40 mg twice weekly and the equivalent weekly dose, 80 mg once weekly. Dose-limiting toxicities of QTc (heart rate–corrected QT interval) prolongation and syncope were observed at 40 and 60 mg twice weekly. Treatment-related adverse events were predominantly grades 1 to 2 in severity, most commonly dysgeusia (40%), dry mouth (29.1%), fatigue (27.3%), and anemia (25.5%). Eleven (20%) patients had treatment-emergent QTc (Fridericia formula) 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 the downregulation of cancer cell proliferation gene sets. One (2%) patient achieved a partial response; eight (15%) patients achieved stable disease, which lasted longer than 6 months in two patients. Conclusions: FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The maximum tolerated doses were identified (40 mg twice weekly/80 mg once weekly) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.