A phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with advanced urothelial tract transitional cell carcinoma.
BACKGROUND
R115777 is a potent farnesyl transferase inhibitor and has significant antitumor effects in vitro and in vivo.


METHODS
The objective of the current study was to determine the objective response proportion in patients with metastatic transitional cell carcinoma (TCC) of the urothelial tract who received treatment with R115777 at a dose of 300 mg orally given twice daily for 21 days followed by 7 days of rest for every 4-week cycle. Thirty-four patients with TCC were enrolled in this Phase II study. Patients were allowed to have received a maximum of one prior systemic chemotherapy regimen, not including chemoradiation or neoadjuvant chemotherapy. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0-2 and adequate bone marrow, hepatic, and kidney function.


RESULTS
Twice daily administration of oral R115777 was tolerated well. R115777 was absorbed rapidly after oral administration. Grade 3-4 neutropenia (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) was observed in 5 patients (15%). Grade 3-4 nonhematologic toxicity was rare, consisting of rash and diarrhea in 1 patient each. Two patients (6%) without prior chemotherapy demonstrated partial responses. Thirteen patients (38%) achieved disease stabilization according to World Health Organization criteria that lasted a median of 4 months. No complete responses were observed.


CONCLUSIONS
The objective response rate of R115777 was not sufficient to warrant future investigation in TCC as a single agent. Preliminary evidence of the activity of R115777 in 2 chemotherapy-naive patients may warrant further investigation in combination with first-line chemotherapy.
Rosenberg
Jonathan E
JE
Department of Medicine, University of California, San Francisco, California 94115, USA. jrosenbe@medicine.ucsf.edu
von der Maase
Hans
H
Seigne
John D
JD
Mardiak
Jozef
J
Vaughn
David J
DJ
Moore
Malcolm
M
Sahasrabudhe
Deepak
D
Palmer
Peter A
PA
Perez-Ruixo
Juan Jose
JJ
Small
Eric J
EJ
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000556:secondary; D003967:Diarrhea / Q000139:chemically induced; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011446:Prospective Studies; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012074:Remission Induction; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy; D014571:Urologic Neoplasms / Q000188:drug therapy*; D019459:Urothelium / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; C402769:tipifarnib