title: Safety and tolerability of PCK3145, a synthetic peptide derived from prostate secretory protein 94 (PSP94) in metastatic hormone-refractory prostate cancer.
abstract: BACKGROUND
  The safety, tolerability, and pharmacokinetic and preliminary efficacy of PCK3145 were determined in patients with metastatic hormone-refractory prostate cancer.
  
  
  METHODS
  PCK3145 was administered in ascending doses of 5, 20, 40, and 80 mg/m2 3 times per week for 4 weeks to cohorts of 4 patients. Dose escalation was based on dose-limiting toxicity (DLT). Pharmacokinetic profiles, tumor burden, and tumor markers (including prostate-specific antigen [PSA] and matrix metalloproteinase-9 [MMP-9] levels) were assessed. Sixteen patients received PCK3145. The median age was 66 years, and the median PSA level was 232.5 microg/L. A total of 32 cycles of therapy were administered.
  
  
  RESULTS
  The most common adverse events reported were pain and nausea. The only DLT was a grade 4 cardiac arrhythmia in a patient treated at the 80-mg/m2 dose level. Pharmacokinetic analysis using a 2-compartment model indicated that the mean area under the curve values increased as the dose range increased, and the mean elimination half-life ranged from 0.35 hours to 1.45 hours. The best tumor response was stable disease in 10 patients and progressive disease in 5 patients. No PSA responses were observed, but 1 patient showed a marked reduction in PSA of 41% at cycle 2. A substantial reduction in MMP-9 levels was observed in patients with baseline levels of MMP-9 > 100 microg/L.
  
  
  CONCLUSIONS
  PCK3145 was safe and well tolerated at all doses. Efficacy observations were encouraging, and the biologic activity of PCK3145 in reducing MMP-9 level may suggest a potential role of this peptide in the regulation of metastatic tumor growth.
authors.affiliation: Medical Oncology Paterson Institute for Cancer Research, Christie Research Center, Manchester, UK.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hawkins
authors.forename: Luc
authors.initials: L
authors.lastname: Daigneault
authors.forename: Richard
authors.initials: R
authors.lastname: Cowan
authors.forename: Richard
authors.initials: R
authors.lastname: Griffiths
authors.forename: Chandra
authors.initials: C
authors.lastname: Panchal
authors.forename: Anne
authors.initials: A
authors.lastname: Armstrong
authors.forename: Jackie
authors.initials: J
authors.lastname: Fenemore
authors.forename: Alan
authors.initials: A
authors.lastname: Irvine
authors.forename: Kasia
authors.initials: K
authors.lastname: Sereda
authors.forename: Hélène
authors.initials: H
authors.lastname: Dulude
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary*; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D010446:Peptide Fragments / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D029584:Prostatic Secretory Proteins
chemical_list: D000970:Antineoplastic Agents; D010446:Peptide Fragments; D029584:Prostatic Secretory Proteins; C506581:tigapotide; D020780:Matrix Metalloproteinase 9