title: A phase 1 multiple-dose study of orteronel in Japanese patients with castration-resistant prostate cancer.
abstract: OBJECTIVE
  Orteronel (TAK-700) is a non-steroidal, selective, reversible inhibitor of 17,20-lyase. We evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effect of orteronel with or without prednisolone in Japanese patients with castration-resistant prostate cancer (CRPC).
  
  
  METHODS
  We conducted a phase 1 study in men with progressive and chemotherapy-naïve CRPC. Patients received orteronel orally at doses of 200-400 mg twice daily (BID) with or without oral prednisolone (5 mg BID). Dose-limiting toxicity (DLT) was assessed during Cycle 1 (28 days). Patients could continue study treatment until any of criteria for treatment discontinuation were met. Gonadotropin-releasing hormone therapy was continued in patients without prior orchidectomy.
  
  
  RESULTS
  Fifteen patients were enrolled and administered at least one dose of orteronel. No DLTs were reported during Cycle 1 in this study. Adverse events (AEs) were reported in all 15 patients. Most common AEs (>30%) were hyperlipasemia (47%), hyperamylasemia (40%), and constipation (33%). Acute pancreatitis (Grades 2 and 3) and pancreatitis (Grade 1) were complicated in three patients during the study. Dose-dependent increase in plasma orteronel concentrations was indicated over the 200-400 mg BID dose range. Prednisolone coadministered did not alter PK of orteronel. Serum testosterone was rapidly suppressed below the lower limit of quantification across all doses. Of 15 subjects, 13 achieved at least a 50% reduction from baseline in prostate-specific antigen.
  
  
  CONCLUSIONS
  Orteronel at doses up to 400 mg BID was tolerable in Japanese CRPC patients. The present results support further evaluation of orteronel with or without prednisolone.
authors.affiliation: Department of Urology, Gunma University Graduate School of Medicine, Gunma, Japan, kazu@gunma-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Ozono
authors.forename: Akito
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Koike
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsui
authors.forename: Masao
authors.initials: M
authors.lastname: Nagata
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Takubo
authors.forename: Kana
authors.initials: K
authors.lastname: Miyashita
authors.forename: Takafumi
authors.initials: T
authors.lastname: Matsushima
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Akaza
mesh_terms: D000368:Aged; D000728:Androgens / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007564:Japan; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009919:Orchiectomy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D007093:Imidazoles; D009281:Naphthalenes; C571806:orteronel