title: Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer.
abstract: OBJECTIVE
  R115777 is an orally active farnesyl transferase inhibitor that specifically blocks farnesylation of proteins involved in growth-factor-dependent cell-signal-transduction pathways. We conducted a phase II study in 76 patients with advanced breast cancer.
  
  
  METHODS
  Two cohorts of patients were recruited sequentially. The first cohort (n = 41) received a continuous dosing [CD] regimen of R115777 400 or 300 mg bid. The second cohort (n = 35) received 300 mg bid in a cyclical regimen of 21 days of treatment followed by 7 days of rest (intermittent dosing [ID]).
  
  
  RESULTS
  In the CD cohort, four patients (10%) had a partial response (PR) and six patients (15%) had stable disease at > or = 24 weeks (SD). In the ID cohort, five patients (14%) had a PR and three patients (9%) had prolonged SD. The first six patients in the CD cohort treated at 400 mg bid all developed grade 3 to 4 neutropenia, so the subsequent 35 patients were treated at 300 mg bid. The incidence of hematologic toxicity was significantly lower in the ID than in the CD (300-mg bid) cohort: grade 3 to 4 neutropenia (14% v 43%; P =.016) and grade 3 to 4 thrombocytopenia (3% v 26%; P =.013). One patient in the ID cohort developed grade 2 to 3 neurotoxicity compared with 15 patients in the CD cohort (3% v 37%; P =.0004).
  
  
  CONCLUSIONS
  The farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen.
authors.affiliation: Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, United Kingdom. stephen.johnston@rmh.nthames.nhs.uk
authors.forename: Stephen R D
authors.initials: SR
authors.lastname: Johnston
authors.forename: Tamas
authors.initials: T
authors.lastname: Hickish
authors.forename: Paul
authors.initials: P
authors.lastname: Ellis
authors.forename: Stephen
authors.initials: S
authors.lastname: Houston
authors.forename: Lloyd
authors.initials: L
authors.lastname: Kelland
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Janine
authors.initials: J
authors.lastname: Salter
authors.forename: Bart
authors.initials: B
authors.lastname: Michiels
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Perez-Ruixo
authors.forename: Peter
authors.initials: P
authors.lastname: Palmer
authors.forename: Angela
authors.initials: A
authors.lastname: Howes
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D015363:Quinolones; C402769:tipifarnib