A phase 1 study of efatutazone, an oral peroxisome proliferator-activated receptor gamma agonist, administered to patients with advanced malignancies

Cancer. 2012 Nov 1;118(21):5403-13. doi: 10.1002/cncr.27526. Epub 2012 May 8.


Background: Efatutazone (CS-7017), a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, exerts anticancer activity in preclinical models. The authors conducted a phase 1 study to determine the recommended phase 2 dose, safety, tolerability, and pharmacokinetics of efatutazone.

Methods: Patients with advanced solid malignancies and no curative therapeutic options were enrolled to receive a given dose of efatutazone, administered orally (PO) twice daily for 6 weeks, in a 3 + 3 intercohort dose-escalation trial. After the third patient, patients with diabetes mellitus were excluded. Efatutazone dosing continued until disease progression or unacceptable toxicity, with measurement of efatutazone pharmacokinetics and plasma adiponectin levels.

Results: Thirty-one patients received efatutazone at doses ranging from 0.10 to 1.15 mg PO twice daily. Dose escalation stopped when maximal impact on PPARγ-related biomarkers had been reached before any protocol-defined maximum-tolerated dose level. On the basis of a population pharmacokinetic/pharmacodynamic analysis, the recommended phase 2 dose was 0.5 mg PO twice daily. A majority of patients experienced peripheral edema (53.3%), often requiring diuretics. Three episodes of dose-limiting toxicities, related to fluid retention, were noted in the 0.10-, 0.25-, and 1.15-mg cohorts. Of 31 treated patients, 27 were evaluable for response. A sustained partial response (PR; 690 days on therapy) was observed in a patient with myxoid liposarcoma. Ten additional patients had stable disease (SD) for ≥60 days. Exposures were approximately dose proportional, and adiponectin levels increased after 4 weeks of treatment at all dose levels. Immunohistochemistry of archived specimens demonstrated that PPARγ and retinoid X receptor expression levels were significantly greater in patients with SD for ≥60 days or PR (P = .0079), suggesting a predictive biomarker.

Conclusions: Efatutazone demonstrates acceptable tolerability with evidence of disease control in patients with advanced malignancies.

Trial registration: ClinicalTrials.gov NCT00408434.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • PPAR gamma / agonists*
  • Thiazolidinediones / administration & dosage*
  • Thiazolidinediones / adverse effects
  • Thiazolidinediones / pharmacokinetics


  • Antineoplastic Agents
  • PPAR gamma
  • Thiazolidinediones
  • efatutazone

Associated data

  • ClinicalTrials.gov/NCT00408434