A phase I study of silibinin in hormone refractory prostate cancer

Abstract

4698 Background: Silibinin is a polyphenolic flavonoid derived from the seeds of milk thistle. Silibinin has been used clinically in Europe and Asia for several decades to treat patients with chronic liver disease and after hepatotoxic ingestion. Preclinical data show antioxidant properties in addition to the inhibition of several mitogenic and survival signaling pathways including insulin-like growth factor receptor type 1, epidermal growth factor receptor, and NF kappa B. Methods: This is a preliminary report of a single institution phase I trial of Silibinin (Silybin-Phytosome TM) in patients with hormone refractory prostate cancer (HRPC). Patient eligibility included a PSA ≥ 1, Gleason score of ≤ 8, progressive disease despite hormonal therapy, and no radiation or investigational therapy in the 4 weeks preceding entry. The initial dose of Silibinin was 2.5 grams daily, in three divided doses. The next daily dose level was 5 grams, with subsequent increases by 5 gram increments. Once 3 patients were treated for a month at a particular dose level without dose limiting toxicity, all patients at lower doses were advanced to that level and new patients were started at the next dose level. Results: To date we have entered 18 patients in the Phase I portion of the study. Since an initial slow-release formulation did not result in measurable level of free Silibinin in blood, the original protocol was amended to administer Silibinin powder, as obtained from Indena, mixed with applesauce. Seven patients have now been registered on the newer protocol at up to 20g/day, with no significant adverse effects. An initial data review shows peak serum Silibinin levels of > 100 microM (approximately 50 μg/ml, a level found to be biologically active in animal studies) in some patients, with peak serum levels noted at 30 or 60 minutes in most patients. A large amount of inter-patient variability has been noted in peak serum levels. Conclusions: Oral Silibinin results in biologically relevant serum levels. Considerable variation was seen in peak serum levels between patients. This study will continue until the maximal tolerated dose of orally delivered Silibinin is established, before pursuing a phase II study in patients with HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Indena