title: First report of the safety, tolerability, and pharmacokinetics of the Src kinase inhibitor saracatinib (AZD0530) in Japanese patients with advanced solid tumours.
abstract: BACKGROUND
  Saracatinib (AZD0530) is a selective, oral Src inhibitor that has demonstrated antitumour activity in preclinical studies.
  
  
  METHODS
  This open-label, dose-escalation, phase I study evaluated the safety and tolerability of saracatinib in Japanese patients with advanced solid tumours (clinicaltrials.gov NCT00704366). Patients received continuous once-daily oral dosing with saracatinib starting 7 days after a single dose in ascending dose cohorts until dose-limiting toxicity (DLT) or disease progression. Pharmacokinetics and efficacy were also evaluated.
  
  
  RESULTS
  A total of 12 patients received saracatinib at doses of 50 (n = 3), 125 (n = 6), and 175 mg (n = 3). Median durations of exposure were 65, 44, and 16 days in the 50, 125, and 175 mg cohorts, respectively. The most common adverse events were diarrhoea (67 %), nausea (67 %), decreased appetite (58 %), lymphopenia (50 %) and pyrexia (50 %). The most common grade ≥3 adverse events were leukopenia, lymphopenia, neutropenia, and haemoglobin decreased (all 17 %). DLTs occurred in two patients, both in the 175 mg cohort: grade 3 aspartate aminotransferase increased with grade 3 gamma-glutamyltransferase increased (n = 1); and grade 3 hypoxia (n = 1). Following a single dose, saracatinib median t(max) across the doses was 2-4 h, and thereafter plasma concentrations declined in a biphasic manner, with mean terminal half-life of approximately 45 h. Geometric mean saracatinib exposures were 0.8-2.1 times greater than those reported in Caucasian patients. The best response was stable disease (50 mg, n = 2; 125 mg, n = 1).
  
  
  CONCLUSIONS
  Saracatinib was tolerated in Japanese patients with advanced solid tumours at doses up to 125 mg.
authors.affiliation: Osaka Medical College, Osaka, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujisaka
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Onozawa
authors.forename: Takayasu
authors.initials: T
authors.lastname: Kurata
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yasui
authors.forename: Isao
authors.initials: I
authors.lastname: Goto
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Nozomu
authors.initials: N
authors.lastname: Machida
authors.forename: Junichiro
authors.initials: J
authors.lastname: Watanabe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimada
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Shi
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People; D052117:Benzodioxoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C515233:saracatinib; D019061:src-Family Kinases