title: 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.
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.
authors: Hokkaido University Hospital Cancer Center, Kita 14 Nishi 5, Kita-ku, Sapporo, Hokkaido, 060-8648, Japan, ykomatsu@ac.cyberhome.ne.jp.
authors: Yoshito
authors: Y
authors: Komatsu
authors: Takayuki
authors: T
authors: Yoshino
authors: Kentaro
authors: K
authors: Yamazaki
authors: Satoshi
authors: S
authors: Yuki
authors: Nozomu
authors: N
authors: Machida
authors: Takahide
authors: T
authors: Sasaki
authors: Ichinosuke
authors: I
authors: Hyodo
authors: Yutaka
authors: Y
authors: Yachi
authors: Hiroshi
authors: H
authors: Onuma
authors: Atsushi
authors: A
authors: Ohtsu
mesh_terms: D052242:Adiponectin / Q000097:blood; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D015415:Biomarkers / Q000097:blood; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000819:agonists; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D000970:Antineoplastic Agents; D015415:Biomarkers; D047495:PPAR gamma; D045162:Thiazolidinediones; C510342:efatutazone; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin