PCK3145, a novel multitargeted signalling agent for the treatment of castrate metastatic prostate cancer (CMPC) Free

A11

Background: PCK3145 is a synthetic 15-mer peptide which bears homology to Prostate Secretory Protein (PSP94). It subserves several functions and appears to work in animal models as an inhibitor of angiogenesis by rapid onset of binding to the laminin receptor in a “hit-and-run” fashion to downregulate Erk, and to reduce plasma matrix metalloproteinase (MMP-9) levels, as well as the expression of MMP-9 within tumor. PCK3145 was evaluated previously in a dose-escalating study in the United Kingdom and was shown to be safe without toxicity and to exert a cytostatic effect on tumor growth. We confirmed safety in a phase I trial using two cohorts of 10 patients (pts) each which evaluated PCK3145 at 7.5 mg/m² iv twice weekly versus 15mg/m² iv weekly given for four weeks with four weeks off. Since that time, both cohorts have been accrued and a third cohort of 8 pts treated at 150mg/m² iv weekly for 16 consecutive weeks to determine the maximum tolerated dose has also been completed.
 Methods: Three cohorts of pts with CMPC with radiographic progression of disease despite multiple hormone manipulations and chemotherapy were studied. Two cohorts of 10 pts each compared 7.5mg/m² twice weekly with 15mg/m² weekly based on dosing schedules extrapolated from prior studies. In an attempt to determine the maximum tolerated dose, an additional cohort of 8 pts received 150mg/m² weekly for 16 consecutive weeks. For pts who derived benefit, additional cycles were permitted.
 Results: PCK3145 was safe at all dose levels. There did not appear to be any difference in the pharmacokinetic profile between the 7.5mg/m² and 15mg/m² dosing schedules. Four patients from each of the 7.5mg/m², 15mg/m² and 150mg/m² dose cohorts received 2 or more cycles of treatment, respectively. Of the 10 pts treated on either the 7.5mg/m² or 15mg/m² cohorts, several pts were taken off study for anxiety due to rising PSAs in the absence of radiographic progression. One pt (with extensive pelvic sidewall adenopathy) treated at the 15mg/m² dose and 2 pts with bone metastases from the 7.5mg/m² twice weekly schedule have not shown radiographic progression since their initiation on study 22 months ago. The PSA doubling time (PSADT) was extended 1.5 to 2-fold in patients treated at the 15mg/m² dose and 2-5 fold in the 7.5mg/m² dose level, respectively. Of the 8 pts treated at 150mg/m² dose, two pts with bone metastases remain on study with stable bone scans for over one year. Pts treated at all dose-levels had precipitous declines in plasma MMP-9 levels while on drug which rose once the drug was discontinued.
 Conclusions: PCK3145 was safe at all dose levels without toxicity. Though a phase I trial, pts with castrate metastatic disease to bone and/or lymph nodes who progressed despite prior treatment with hormones and chemotherapy have radiographically stable disease and lengthening of PSA doubling times for close to two years. These results were unexpected given the natural history of patients who have failed prior treatment with hormones and/or chemotherapy. All dose levels were well-tolerated and there appeared to be an anti-tumor effect irrespective of the dose levels; 15mg/m² given weekly will likely be the dose for future phase II/III development.