Safety and Tolerability of PCK3145, a Synthetic Peptide Derived from Prostate Secretory Protein 94 (PSP94) in Metastatic Hormone-Refractory Prostate Cancer

• Published in: Clinical prostate cancer Vol. 4; no. 2; pp. 91 - 99
• Main Authors: Hawkins, Robert E., Daigneault, Luc, Cowan, Richard, Griffiths, Richard, Panchal, Chandra, Armstrong, Anne, Fenemore, Jackie, Irvine, Alan, Sereda, Kasia, Dulude, Hélène
• Format: Journal Article
• Language: English
• Published: United States 01.09.2005
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - secondary; Aged; Angiogenesis; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Dose-limiting toxicity; Humans; Invasiveness; Male; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinase–9; Middle Aged; Peptide Fragments - adverse effects; Peptide Fragments - pharmacokinetics; Peptide Fragments - therapeutic use; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Secretory Proteins; Angiogenesis; Matrix metalloproteinase–9; Invasiveness; Dose-limiting toxicity
• ISSN: 1540-0352; 2374-8435
• DOI: 10.3816/CGC.2005.n.016

The safety, tolerability, and pharmacokinetic and preliminary efficacy of PCK3145 were determined in patients with metastatic hormone-refractory prostate cancer. 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 μg/L. A total of 32 cycles of therapy were administered. 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 μg/L. 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.