Multicenter phase 1 trial of a small-molecule inverse agonist of PPARγ for advanced solid tumors

PPARγ is a master regulator of luminal lineage in urothelial carcinoma. FX-909 is a first-in class oral small molecule PPARγ inverse agonist. The multicenter phase 1 FX-909-CLINPRO-1 trial in the USA evaluated FX-909 among 56 patients with advanced solid tumors, including 46 with urothelial carcinoma. FX-909 exhibited an acceptable safety and tolerability profile (primary endpoint). Grade ≥3 adverse events included anemia (26.8%), thrombocytopenia (21.4%), fatigue (10.7%), and hyperglycemia (7.1%). Doses of 30 mg and 50 mg daily were selected for recommended phase 2 dose optimization. Objective response were observed in 17.5% of patients with urothelial carcinoma across all dose levels. Tumor responses were enriched in patients wth high PPARγ expression. The authors conclude that FX-909 demonstrated acceptable safety and tolerability with preliminary antitumor activity, supporting further clinical development in urothelial cancer.