title: Marimastat in the treatment of patients with biochemically relapsed prostate cancer: a prospective randomized, double-blind, phase I/II trial.
abstract: OBJECTIVE
  To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer.
  
  
  METHODS
  Patients with a biochemical relapse within 2 years of primary therapy, a prostate-specific antigen (PSA) increase of at least 50% within 6 months of study entry, and no prior systemic therapy were eligible. Patients were randomized to receive marimastat at total daily doses of 5, 20, or 40 mg for 6 months unless dose-limiting toxicity or new evidence of disease occurred.
  
  
  RESULTS
  Thirty-nine patients were treated. Grade 3-4 reversible musculoskeletal toxicity was the only dose-limiting toxicity. Increasing dose was associated with increased probability of experiencing dose-limiting toxicity (5.9%, 42.9% and 88.9% for the 5, 20, and 40 mg groups, respectively; P = 0.03). Accrual was discontinued early on the two higher dose levels due to toxicity. A significant decrease in PSA slope was shown in the 20 mg group when compared with the 5 mg group (0.117 and -0.0046, respectively; P = 0.03) The 40 mg group (versus the 5 mg group) showed a similar change (0.109) with a trend towards significance (P = 0.07). An increased serum matrix metalloproteinase 2 level at month 3 compared with the baseline correlated with a decrease in PSA slopes (Slope, 0.001; 95% confidence interval, 0.0002-0.0018; P = 0.02).
  
  
  CONCLUSIONS
  These data suggest that marimastat has a biological effect and may effectively delay progression in patients with biochemical relapsed prostate cancer, as shown by the change in PSA slope; however, dose-limiting toxicity at active doses is significant. Confirmatory studies with less toxic matrix metalloproteinase inhibitors employing more conventional end points are indicated. This design is feasible and potentially efficient for screening antimetastatic agents.
authors.affiliation: Department of Radiation Oncology and Molecular Sciences, Division of Medical Oncology and Biostatistics and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Rosenbaum
authors.forename: Marianna
authors.initials: M
authors.lastname: Zahurak
authors.forename: Victoria
authors.initials: V
authors.lastname: Sinibaldi
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.forename: Menachem
authors.initials: M
authors.lastname: Laufer
authors.forename: Theodore L
authors.initials: TL
authors.lastname: DeWeese
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D018771:Arthralgia / Q000139:chemically induced; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013995:Time; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C100342:marimastat; D017430:Prostate-Specific Antigen; D008666:Metalloendopeptidases