A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer.
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.
Winquist
Eric
E
London Regional Cancer Centre, London, Ontario, Canada. eric.winquist@lrcc.on.ca
Moore
Malcolm J
MJ
Chi
Kim N
KN
Ernst
D Scott
DS
Hirte
Hal
H
North
Scott
S
Powers
Jean
J
Walsh
Wendy
W
Boucher
Therese
T
Patton
Robert
R
Seymour
Lesley
L
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
D010880:Piperidines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes