BACKGROUND: The safety, tolerability, and pharmacokinetic and preliminary efficacy of PCK3145 were determined in patients with metastatic hormone-refractory prostate cancer. PATIENTS AND 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. CONCLUSION: 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.
BACKGROUND: The safety, tolerability, and pharmacokinetic and preliminary efficacy of PCK3145 were determined in patients with metastatic hormone-refractory prostate cancer. PATIENTS AND 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. CONCLUSION: 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: Timothy A Yap; Alan D Smith; Roberta Ferraldeschi; Bissan Al-Lazikani; Paul Workman; Johann S de Bono Journal: Nat Rev Drug Discov Date: 2016-07-22 Impact factor: 84.694
Authors: Andreas M Luebke; Ali Attarchi-Tehrani; Jan Meiners; Claudia Hube-Magg; Dagmar S Lang; Martina Kluth; Maria Christina Tsourlakis; Sarah Minner; Ronald Simon; Guido Sauter; Franziska Büscheck; Frank Jacobsen; Andrea Hinsch; Stefan Steurer; Thorsten Schlomm; Hartwig Huland; Markus Graefen; Alexander Haese; Hans Heinzer; Till S Clauditz; Eike Burandt; Waldemar Wilczak; Doris Höflmayer Journal: Cancer Biol Med Date: 2019-05 Impact factor: 4.248