title: Phase I trial of the matrix metalloproteinase inhibitor marimastat combined with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer.
abstract: OBJECTIVE
  Marimastat is an orally bioavailable inhibitor of matrix metalloproteinases. A phase I study was initiated to determine whether conventional doses of carboplatin and paclitaxel are tolerated when combined with marimastat and to assess the influence of marimastat on paclitaxel pharmacokinetics.
  
  
  METHODS
  Three dose levels were evaluated. Marimastat (10 or 20 mg oral administration b.i.d.) was administered continuously with paclitaxel (175 or 200 mg/m(2) as a 3-hour i.v. infusion) and carboplatin (at a dose providing an area under the free drug plasma concentration-time curve of 7 mg min/mL) administered each 3 weeks. Toxicity and response were evaluated throughout the intended four cycles of combined therapy. The plasma pharmacokinetics of paclitaxel was determined in each patient both without concurrent marimastat and after receiving marimastat for 1 week.
  
  
  RESULTS
  Twenty-two chemotherapy-naive patients with stage IIIb (27%) or stage IV (73%) non-small cell lung cancer were enrolled. Their median age was 56 years (range, 39-73 years), 50% were female, and their performance status (Eastern Cooperative Oncology Group) ranged from 0 to 2. Treatment was well tolerated, as 18 (82%) of the patients completed all four cycles of chemotherapy without dose-limiting toxicity. Grade 2 musculoskeletal toxicities were reported in 3 of 12 patients receiving marimastat (20 mg b.i.d.). Nine patients required dose reductions, predominantly related to low-grade myelosuppression. Partial responses occurred in 12 of 21 (57%) evaluable patients with disease stabilization in another 5 (19%). Marimastat had no effect on paclitaxel pharmacokinetics.
  
  
  CONCLUSIONS
  The administration of marimastat (10 mg b.i.d.) with paclitaxel (200 mg/m(2)) and carboplatin at an area under the free drug plasma concentration-time curve of 7 mg min/mL was well tolerated with no apparent pharmacokinetic interaction. Study of this drug combination in the adjuvant setting should be considered if tissue inhibition of matrix metalloproteinase activity can first be shown.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Goffin
authors.forename: Ian C
authors.initials: IC
authors.lastname: Anderson
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Joseph Paul
authors.initials: JP
authors.lastname: Eder
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
authors.forename: Margaret
authors.initials: M
authors.lastname: Shipp
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Skarin
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D016190:Carboplatin; C100342:marimastat; D008666:Metalloendopeptidases; D017239:Paclitaxel