A phase II, randomized, blinded study of the farnesyltransferase inhibitor tipifarnib combined with letrozole in the treatment of advanced breast cancer after antiestrogen therapy.
BACKGROUND
This study assessed the clinical efficacy of the farnesyltransferase inhibitor, tipifarnib, combined with letrozole in patients with advanced breast cancer and disease progression following antiestrogen therapy.


METHODS
Postmenopausal women with estrogen-receptor-positive advanced breast cancer that had progressed after tamoxifen were given 2.5 mg letrozole once daily and were randomly assigned (2:1) to tipifarnib 300 mg (TL) or placebo (L) twice daily for 21 consecutive days in 28-day cycles. The primary endpoint was objective response rate.


RESULTS
Of 120 patients treated with TL (n = 80) or L (n = 40), 113 were evaluable for response. Objective response rate was 30% (95% CI; 20-41%) for TL and 38% (95% CI; 23-55%) for L. There was no significant difference in response duration, time to disease progression or survival. Clinical benefit rates were 49% (TL) and 62% (L). Tipifarnib was generally well tolerated; a higher incidence of drug-related asymptomatic grade 3/4 neutropenia was observed for TL (18%) than for L (0%). Tipifarnib population pharmacokinetics were similar to previous studies, with no significant difference in trough letrozole concentrations between the TL and L groups.


CONCLUSIONS
Adding tipifarnib to letrozole did not improve objective response rate in this population of patients with advanced breast cancer.
Johnston
Stephen R D
SR
Department of Medicine, Breast Unit, Royal Marsden NHS Foundation Trust, Fulham Road, Chelsea, London, UK. stephen.johnston@rmh.nhs.uk
Semiglazov
Vladimir F
VF
Manikhas
George M
GM
Spaeth
Dominique
D
Romieu
Gilles
G
Dodwell
David J
DJ
Wardley
Andrew M
AM
Neven
Patrick
P
Bessems
Annick
A
Park
Youn C
YC
De Porre
Peter M
PM
Perez Ruixo
Juan J
JJ
Howes
Angela J
AJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D004311:Double-Blind Method; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage*; D015363:Quinolones / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage*
D020847:Estrogen Receptor Modulators; D009570:Nitriles; D015363:Quinolones; D014230:Triazoles; D000077289:Letrozole; D051231:Farnesyltranstransferase; C402769:tipifarnib