title: Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18.
abstract: OBJECTIVE
  To determine whether BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor (MMPI), added to systemic chemotherapy improved survival in advanced non-small-cell lung cancer (NSCLC). In early phase studies, BMS- 275291 was not associated with dose-limiting joint toxicity seen with other MMPIs.
  
  
  METHODS
  Chemotherapy-naive patients with stage IIIB/IV NSCLC, performance status (PS) 0 to 2, and adequate organ function were eligible. All patients received paclitaxel 200 mg/m2 plus carboplatin (area under the curve, 6 mg/mL-min) intravenously every 21 days for up to 8 cycles, and were randomly assigned to receive BMS-275291, 1,200 mg orally daily, or placebo until disease progression. The primary study end point was survival (OS); secondary end points included progression-free survival (PFS), response rates (RR), toxicity, and quality of life.
  
  
  RESULTS
  From 2000 to 2002, 774 patients were randomly assigned. Pretreatment characteristics were well balanced between arms: median age, 61 years; male sex, 73%; stage IV, 79%; PS 0 to 1, 88%. Interim safety analysis revealed no survival advantage and increased toxicity in the experimental arm, and study treatment was stopped. Median OS, PFS and RR in the final analysis in the BMS-275291 arm were 8.6 months, 4.9 months, and 25.8% respectively, and in the control arm 9.2 months, 5.3 months, 33.7%. Toxicity was significantly higher in the BMS-275291 arm, including flu-like symptoms, rash, hypersensitivity reactions (8.6% v 2.4%), and febrile neutropenia (9.7% v 5.5%).
  
  
  CONCLUSIONS
  BMS-275291 added to chemotherapy increases toxicity and does not improve survival in advanced NSCLC.
authors.affiliation: National Cancer Institute of Canada--Clinical Trials Group, Kingston, Canada. Natasha.Leighl@uhn.on.ca
authors.forename: Natasha B
authors.initials: NB
authors.lastname: Leighl
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Andrew
authors.initials: A
authors.lastname: Arnold
authors.forename: Alain
authors.initials: A
authors.lastname: Depierre
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Betticher
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gatzemeier
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Crawford
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Tu
authors.forename: Andrea
authors.initials: A
authors.lastname: Bezjak
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Humphrey
authors.forename: Maurizio
authors.initials: M
authors.lastname: Voi
authors.forename: Susan
authors.initials: S
authors.lastname: Galbraith
authors.forename: Katherine
authors.initials: K
authors.lastname: Hann
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007093:Imidazoles; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases; D008875:Middle Aged; D009930:Organic Chemicals / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage; D010919:Placebos; D016896:Treatment Outcome
chemical_list: D007093:Imidazoles; D009930:Organic Chemicals; D010919:Placebos; 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; D016190:Carboplatin; D020782:Matrix Metalloproteinases; D017239:Paclitaxel