title: Phase I trial of the matrix metalloproteinase inhibitor BAY12-9566 in patients with advanced solid tumors.
abstract: OBJECTIVE
  Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that are believed to be involved in primary and metastatic tumor growth by degrading the basement membrane and changing the extracellular matrix to facilitate invasion of malignant cells and angiogenesis. Overexpression of MMPs has been documented in various solid tumors. BAY12-9566 is a selective inhibitor of MMPs, in particular MMP-2, -3. and -9. The purpose of this trial was to define the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, pharmacokinetics and pharmacodynamics of orally administered BAY12-9566 in patients with incurable solid tumors.
  
  
  METHODS
  The starting dose of BAY12-9566 for this single institution, outpatient phase I study was 100 mg/day orally. Patients were allowed to receive drug for up to 12 months. A total of 27 patients with various solid malignancies including colorectal, breast, lung, cervical and ovarian cancers were enrolled at doses from 100 to 1,600 mg/day. Patients were evaluated weekly while on treatment. Relevant radiologic examination was performed every 8 weeks to document and follow sites of measurable or evaluable disease.
  
  
  RESULTS
  Toxicities from BAY12-9566 included liver injury test abnormalities, anemia, shoulder and back pain. thrombocytopenia, mild nausea and fatigue, diarrhea, rash and deep vein thrombosis. No toxicity greater than grade III was observed. As doses were increased from 100 to 400 to 1,600 mg/day, even in divided doses, less than proportional increases in AUC were observed. At the highest dose level of 1600 mg/day, the day 29 AUC (3778.00 mg x h/l) remained similar to the day 29 AUC (3312.60 mg x h/l) at the dose level of 1200 mg/day. No responses were seen, but 14 patients remained on study with stable disease for 4 to 26 months.
  
  
  CONCLUSIONS
  BAY12-9566 was well tolerated at doses as high as 800 mg orally twice daily. Although mild alterations in liver injury tests, platelet count and hematocrit were noted, these were not dose-limiting. The drug was well absorbed. However, the absence of proportional increases in AUC with doses greater than 800 mg and the achievement of Css in the range associated with biologic activity in preclinical models led to the selection of 800 mg twice daily for further evaluation in phase III trials.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, MD 21231, USA. heathel@jhmi.edu
authors.forename: E I
authors.initials: EI
authors.lastname: Heath
authors.forename: S
authors.initials: S
authors.lastname: O'Reilly
authors.forename: R
authors.initials: R
authors.lastname: Humphrey
authors.forename: P
authors.initials: P
authors.lastname: Sundaresan
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
authors.forename: S
authors.initials: S
authors.lastname: Sartorius
authors.forename: M J
authors.initials: MJ
authors.lastname: Kennedy
authors.forename: D K
authors.initials: DK
authors.lastname: Armstrong
authors.forename: M A
authors.initials: MA
authors.lastname: Carducci
authors.forename: J M
authors.initials: JM
authors.lastname: Sorensen
authors.forename: K
authors.initials: K
authors.lastname: Kumor
authors.forename: S
authors.initials: S
authors.lastname: Kennedy
authors.forename: L B
authors.initials: LB
authors.lastname: Grochow
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009930:Organic Chemicals; D010654:Phenylbutyrates; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009930:Organic Chemicals; D010654:Phenylbutyrates; C113281:Bay 12-9566