title: A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer.
abstract: OBJECTIVE
  Protein farnesylation by farnesyltransferase (FTase) is required for membrane localization and effective signal transduction by G-proteins, including Ras. Lonafarnib inhibits FTase and has shown antitumor activity in both preclinical and clinical settings. As disturbances in Ras signaling pathways have been implicated in the pathogenesis of transitional cell carcinoma (TCC), the antitumor activity of lonafarnib was studied in a National Cancer Institute of Canada Clinical Trials Group Phase II trial in patients with previously treated TCC.
  
  
  METHODS
  Patients had at least 1 prior chemotherapy regimen for advanced unresectable or metastatic TCC, or recurrence less than 1 year after adjuvant or neoadjuvant chemotherapy. Lonafarnib was given at a dose of 200 mg PO twice daily continuously, with cycles repeated every 4 weeks.
  
  
  RESULTS
  Between December 1999 and December 2000, 19 eligible patients were enrolled at 8 National Cancer Institute of Canada Clinical Trials Group centers. Median time on treatment was 7.1 weeks (range, 0.6-23.9). Drug-related Grade 3 toxicities included fatigue, anorexia, nausea, confusion, dehydration, muscle weakness, depression, headache, and dyspnea. Five patients discontinued the study protocol due to toxicity. No responses were observed in 10 patients who were evaluable. Of 9 patients not evaluable for response, 5 had symptomatic progression, fulfilling multinomial criteria to stop the study after the first stage.
  
  
  CONCLUSIONS
  No single-agent activity of lonafarnib was observed in this study of patients with aggressive TCC failing prior chemotherapy.
authors.affiliation: London Regional Cancer Centre, London, Ontario, Canada. eric.winquist@lrcc.on.ca
authors.forename: Eric
authors.initials: E
authors.lastname: Winquist
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Moore
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
authors.forename: D Scott
authors.initials: DS
authors.lastname: Ernst
authors.forename: Hal
authors.initials: H
authors.lastname: Hirte
authors.forename: Scott
authors.initials: S
authors.lastname: North
authors.forename: Jean
authors.initials: J
authors.lastname: Powers
authors.forename: Wendy
authors.initials: W
authors.lastname: Walsh
authors.forename: Therese
authors.initials: T
authors.lastname: Boucher
authors.forename: Robert
authors.initials: R
authors.lastname: Patton
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014516:Ureteral Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003986:Dibenzocycloheptenes
chemical_list: D010880:Piperidines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes