title: A randomized phase II feasibility trial of BMS-275291 in patients with early stage breast cancer.
abstract: OBJECTIVE
  This pilot trial was performed to evaluate the safety, pharmacokinetics and feasibility of incorporating BMS-275291, a matrix metalloproteinase inhibitor (MMPI), into adjuvant breast cancer therapy.
  
  
  METHODS
  Patients with stage I (T1c)-IIIA breast cancer were eligible if planned adjuvant therapy consisted of either tamoxifen alone, doxorubicin + cyclophosphamide every 21 days for four cycles (AC), or AC followed by paclitaxel every 21 days for 4 cycles (AC>T). Patients were stratified by planned adjuvant therapy and randomized (2:1 ratio) to BMS-275291 (1200 mg/day) or matched placebo for 1 year.
  
  
  RESULTS
  Seventy-two patients were recruited from March 2001 to July 2002. Grade >or=2 musculoskeletal toxicity, generally reversible arthralgia, was reported by 36.2% of patients receiving BMS-275291 compared with 16.7% of patients receiving placebo; difference = 19.5% (95% confidence interval: -0.06, 0.44; P = NS). Two patients receiving BMS-275291 developed palpable nodules along tendons. Grade >or=3 rash was reported by 8.5% of patients receiving BMS-275291 compared with 4.2% of patients receiving placebo; difference = 4.3% (95% confidence interval: -0.18, 0.3; P = NS). Overall, 33% of BMS-275291 patients and 21% of placebo patients discontinued treatment due to adverse events. BMS-275291 trough levels tended to decrease over time; 9 of 47 (19%) had >or=50% of trough concentrations > 124 ng/ml (IC(90) for matrix metalloproteinase-9).
  
  
  CONCLUSIONS
  The pattern of arthralgia in BMS-275291-treated patients was consistent with matrix metalloproteinase inhibitor toxicity. Although the differential incidence of arthralgia did not reach statistical significance, the trial was terminated. An adjuvant trial in this patient population is not feasible.
authors.affiliation: Indiana University, Indianapolis, Indiana, USA. kathmill@iupui.edu
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Saphner
authors.forename: David M
authors.initials: DM
authors.lastname: Waterhouse
authors.forename: T-T
authors.initials: TT
authors.lastname: Chen
authors.forename: Anita
authors.initials: A
authors.lastname: Rush-Taylor
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.forename: Melody A
authors.initials: MA
authors.lastname: Cobleigh
authors.forename: Susan
authors.initials: S
authors.lastname: Galbraith
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood / Q000627:therapeutic use* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D009367:Neoplasm Staging; D009930:Organic Chemicals / Q000627:therapeutic use* / Q000633:toxicity*; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D013629:Tamoxifen; C422302:N-((2S)-2-mercapto-1-oxo-4-(3,4,4- trimethyl-2,5-dioxo-1-imidazolidinyl)butyl)-L-leucyl-N,3- dimethyl-L-Valinamide; D004317:Doxorubicin; D003520:Cyclophosphamide