PPARγの低分子インバースアゴニストによる進行固形がん治療：第I相試験

Peroxisome proliferator-activated receptor gamma (PPARγ) is a master regulator of luminal lineage in urothelial carcinoma. FX-909 is a first-in-class oral small-molecule PPARγ inverse agonist. Here we report the first part of FX-909-CLINPRO-1, a phase 1A 3 + 3 dose-escalation study of FX-909, that enrolled 56 patients with advanced solid tumors, including 46 with urothelial carcinoma. The primary end point was safety and tolerability; secondary end points included recommended phase 2 dose determination, pharmacokinetics and preliminary antitumor activity. FX-909 exhibited an acceptable safety and tolerability profile. 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 responses were observed in 17.5% of patients with urothelial carcinoma across all dose levels. Exploratory analyses revealed that tumor responses were enriched in patients with high PPARγ expression. FX-909 demonstrated acceptable safety and tolerability with preliminary antitumor activity, supporting further clinical development in urothelial cancer. ClinicalTrials.gov identifier: NCT05929235 .