title: Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196.
abstract: OBJECTIVE
  To determine whether a matrix metalloproteinase inhibitor improves progression-free survival (PFS) in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy.
  
  
  METHODS
  One hundred seventy-nine eligible patients were randomly assigned to receive oral marimastat (10 mg bid; n = 114) or a placebo (n = 65) within 3 to 6 weeks of completing six to eight cycles of first-line doxorubicin- and/or taxane-containing chemotherapy for metastatic disease. Patients were evaluated every 3 months until disease progression.
  
  
  RESULTS
  When comparing placebo with marimastat, there was no significant difference in PFS (median, 3.1 months v 4.7 months, respectively; hazard ratio, 1.26; 95% CI, 0.91 to 1.74; P = .16) or overall survival (median, 26.6 months v 24.7 months, respectively; hazard ratio, 1.03; 95% CI, 0.73 to 1.46; P = .86). Patients treated with marimastat were more likely to develop grade 2 or 3 musculoskeletal toxicity (MST), a known complication of the drug indicative of achieving a biologic effect, compared with patients administered placebo (63% v 22%, respectively; P < .0001). Patients with grade 2 or 3 MST had significantly inferior survival compared with patients who had grade 0 or 1 MST (median, 22.5 months v 28.2 months; P = .04). In addition, patients who had a marimastat plasma concentration of at least 10 ng/mL at month 1 and/or 3 were significantly more likely to have grade 2 to 3 MST (P < .0001).
  
  
  CONCLUSIONS
  Marimastat does not prolong PFS when used after first-line chemotherapy for metastatic breast cancer. Patients with higher marimastat levels exhibited MST, and MST was associated with inferior survival.
authors.affiliation: Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY 10461, USA. Sparano@jimmy.harvard.edu
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.forename: Patricia
authors.initials: P
authors.lastname: Bernardo
authors.forename: Patricia
authors.initials: P
authors.lastname: Stephenson
authors.forename: William J
authors.initials: WJ
authors.lastname: Gradishar
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Stanley
authors.initials: S
authors.lastname: Zucker
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009367:Neoplasm Staging; D011336:Probability; D016016:Proportional Hazards Models; D012016:Reference Values; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D006877:Hydroxamic Acids; C100342:marimastat