Phase 1 Study of Efatutazone, a Novel Oral Peroxisome Proliferator-Activated Receptor Gamma Agonist, in Combination With FOLFIRI as Second-Line Therapy in Patients With Metastatic Colorectal Cancer

Invest New Drugs. 2014 Jun;32(3):473-80. doi: 10.1007/s10637-013-0056-3. Epub 2013 Dec 15.

Abstract

Background: Efatutazone, a novel oral highly-selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has demonstrated some inhibitory effects on disease stabilization in patients with metastatic colorectal cancer (mCRC) enrolled in previous phase I studies. Here, we evaluate the safety and pharmacokinetics of efatutazone combined with FOLFIRI (5-fluorouracil, levo-leucovorin, and irinotecan) as second-line chemotherapy in Japanese patients with mCRC.

Methods: Dose-limiting toxicities (DLTs) were evaluated at 2 efatutazone dose levels of 0.25 and 0.50 mg (the recommended dose [RD] of efatutazone monotherapy) twice daily in combination with FOLFIRI in a 3-9 patient cohort. Furthermore, tolerability at the RD level was assessed in additional patients, up to 12 in total. Blood samples for pharmacokinetics and biomarkers and tumor samples for archival tissues were collected from all patients.

Results: Fifteen patients (0.25 mg, 3; 0.5 mg, 12) were enrolled. No DLTs were observed. Most patients experienced weight increase (100 %) and edema (80.0 %), which were manageable with diuretics. Common grade 3/4 toxicities were neutropenia (93.3 %), leukopenia (46.7 %), and anemia (33.3 %). Stable disease was observed in 8 of the 14 patients evaluable for tumor response. The plasma adiponectin levels increased over time and increased dose. No clear relationship was detected between treatment efficacies and plasma levels of adiponectin as well as the expression levels of PPARγ and the retinoid X receptor in tumor tissues.

Conclusions: Efatutazone combined with FOLFIRI demonstrates an acceptable safety profile and evidence of disease stabilization in Japanese patients with mCRC. The RD for efatutazone monotherapy can be used in combination with FOLFIRI.

Publication types

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

MeSH terms

  • Adiponectin / blood
  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / blood
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Biomarkers / blood
  • Camptothecin / administration & dosage
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives*
  • Camptothecin / blood
  • Camptothecin / pharmacokinetics
  • Colorectal Neoplasms / blood
  • Colorectal Neoplasms / drug therapy*
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Fluorouracil / blood
  • Fluorouracil / pharmacokinetics
  • Humans
  • Leucovorin / administration & dosage
  • Leucovorin / adverse effects
  • Leucovorin / blood
  • Leucovorin / pharmacokinetics
  • Male
  • Middle Aged
  • PPAR gamma / agonists
  • Thiazolidinediones / administration & dosage*
  • Thiazolidinediones / adverse effects
  • Thiazolidinediones / blood
  • Thiazolidinediones / pharmacokinetics
  • Treatment Outcome

Substances

  • ADIPOQ protein, human
  • Adiponectin
  • Antineoplastic Agents
  • Biomarkers
  • PPAR gamma
  • Thiazolidinediones
  • efatutazone
  • Leucovorin
  • Fluorouracil
  • Camptothecin

Supplementary concepts

  • IFL protocol