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<p>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: <a href="https://clinicaltrials.gov/study/NCT05929235">NCT05929235</a>.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月28日

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  • 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

摘要

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.