Safety, tolerability, pharmacokinetic and escalating single doses of PCK3145 in patients with metastatic hormone resistant prostatic cancer (HRPC)

4473 Introduction and Objective: Prostate secretory protein (PSP94) within PSA and PAP is one of the three most abundant protein in the seminal fluid. PSP94 has demonstrated antiproliferative and anti-tumour activity both in vitro and in vivo animal models. PCK3145 is a synthetic 15-mer peptide that matches the natural sequence of amino acids 31 to 45 of the prostate secretory protein (PSP94) and has demonstrated similar antiproliferative and antitumoral activity in the animal models PC3 and the Dunning rat R-3327 MLL. The mechanism of action of PCK3145 is not fully elucidated but may be related in part to induction of apoptosis. The primary objective of this clinical study was to evaluate the safety and the tolerability of PCK3145 administered i.v. over a range of potentially therapeutic doses. The secondary objectives were to determine the pharmacokinetic profile and to evaluate efficacy data using tumour assessments and tumour markers. Methods: Since October 2002, 12 metastatic Hormone Resistant Prostatic Cancer (HRPC) patients have been receiving treatment in this open-label, non-randomized, dose-escalation study in which successive cohorts of at least 4 patients are receiving 4 ascending doses (5, 20, 40 and 80 mg/m2) of PCK3145 (33-day cycle of treatment consisting of PCK3145 administration three times per week for 26 days, followed by a 7-day Post-Treatment Observation Period). The dose escalation is based on dose-limiting toxicity (DLT). Results: Preliminary characteristics (n = 8) are that the median age is 67 y (53-75) and the median time from HRPC to enrolment is 12.5 months (0.7-34). The Karnofsky Performance Status, remained high. The majority of the patients received hormonal therapy, had radiotherapy and TURP (Transurethral Prostatectomy). Sites of disease were mainly bone and lymph node. Serious Adverse Events (SAEs) reported so far are all unlikely or unrelated to study drug. Preliminary results indicate that the half-life of PCK3145 is 20 minutes and tumor assessments suggest that the patients are having stable disease at least after one cycle. Some patients showed a decline in PSA levels (one of them by almost 50%). All patients who had plasma MMP-9 levels over 100 ug/L before treatment had reductions ranging from 34% to 90% after two cycles of treatment. In the other patients that had low levels of MMP-9 prior to treatment, they remained low and only increased in two cases when cancer relapse was deemed to have occurred. Conclusions: These clinical results are very interesting and suggest the potential role of PCK3145 in the intervention of the metastatic process. The marked reduction in plasma MMP-9 levels of patients receiving PCK3145 treatment clearly indicates a biochemical effect, and provides a potentially novel mechanism of action of this small molecule in these patients.

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