title: Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer.
abstract: BACKGROUND
  AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (Cmax) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609).
  
  
  METHODS
  AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if ≤ 2 of the first 20 evaluable patients achieved an objective tumor response. Cmax was assessed on days 1 and 8 of cycle 1.
  
  
  RESULTS
  None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for ≥ 8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade ≥ 3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively.
  
  
  CONCLUSIONS
  AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.
authors: Institute of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK. r.jones@beatson.gla.ac.uk
authors: Robert
authors: R
authors: Jones
authors: Jacqueline
authors: J
authors: Vuky
authors: Tony
authors: T
authors: Elliott
authors: Graham
authors: G
authors: Mead
authors: José Angel
authors: JA
authors: Arranz
authors: John
authors: J
authors: Chester
authors: Simon
authors: S
authors: Chowdhury
authors: Arkadiusz Z
authors: AZ
authors: Dudek
authors: Volker
authors: V
authors: Müller-Mattheis
authors: Marc-Oliver
authors: MO
authors: Grimm
authors: Jürgen E
authors: JE
authors: Gschwend
authors: Christian
authors: C
authors: Wülfing
authors: Peter
authors: P
authors: Albers
authors: Jianguo
authors: J
authors: Li
authors: Anna
authors: A
authors: Osmukhina
authors: Jeffrey
authors: J
authors: Skolnik
authors: Gary
authors: G
authors: Hudes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D003710:Demography; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011744:Pyrimidinones / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism*; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019459:Urothelium / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C568512:N-(3-aminopropyl)-N-(1-(5-benzyl-3-methyl-4-oxo-(1,2)thiazolo(5,4-d)pyrimidin-6-yl)-2-methylpropyl)-4-methylbenzamide; D011744:Pyrimidinones; D016547:Kinesins