A small-molecule inverse agonist of PPARγ for advanced solid tumors: a phase 1 trial.
- 2026-02-28
- Nature medicine 32(4)
- Matthew D Galsky
- Charlene Mantia
- Michaela Bowden
- Joaquim Bellmunt
- Benjamin Garmezy
- Gopa Iyer
- Daniel P Petrylak
- Drew Rasco
- Shilpa Gupta
- Ildefonso Rodriguez-Rivera
- Yelena Mikhailov
- Adarsh Joshi
- Phuong A Nguyen
- Bijal Kakrecha
- Jennifer Tepper
- Anne Marie Costa
- Carolyn McCrone
- Alex P Rossi
- Jennifer A Mertz
- Evisa Gjini
- Michael L Meyers
- Matthew I Milowsky
- Xin Gao
- PubMed: 41760953
- DOI: 10.1038/s41591-026-04263-3
Study Design
- Type
- Clinical Trial
- Sample size
- n = 56
- Population
- 56 patients with advanced solid tumors, including 46 with urothelial carcinoma
- Methods
- phase 1A 3+3 dose-escalation study of FX-909
- Blinding
- Open-label
- Funding
- Unclear
- Rigorous Journal
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 .