CALCITRIOL IN RECURRENT PROSTATE CANCER

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Initial treatment of localized prostate cancer with surgery or radiation has cure as its goal. After definitive treatment, serum prostate specific antigen (PSA) can be used to monitor for recurrence. No effective cure is available once metastases occur. Hormonal deprivation is standard treatment for men with advanced prostate cancer with painful bone metastases. However, the early application of androgen deprivation has not been shown to prolong survival in patients with rising PSA as the only evidence of recurrence. Novel agents are needed to delay the progression of prostate cancer in this patient population. Calcitriol is the active metabolite of dietary Vitamin D. Many human tumors, including prostate carci-omas, contain the intracellular nuclear receptor for calcitriol, Vitamin D receptor (VDR). Calcitriol is an active antineoplastic agent in a variety of tissue culture and animal models of cancer including adenocarcinoma of the prostate. Previous attempts to use calcitriol as an antineoplastic drug in humans have been foiled by the development of hypercalcemia when the drug is used on its standard daily schedule. Preclinical data suggest that intermittent exposure to high levels of calcitriol may be sufficient to achieve an anti-cancer effect. We have completed a Phase I trial of high-dose weekly oral calcitriol (Rocaltrol) in patients with advanced malignancies. Although this drug can be escalated to at least 2.0 mg/kg weekly for four weeks with minimal toxicity, calcitriol absorption is non-linear and a dose of 0.5 ug/kg is recommended for a Phase II trial. At this dose, potentially therapeutic peak calcitriol levels of approximately 30 above normal and forty-eight hour AUC of 6-8 fold above normal are achieved. We propose to test the efficacy of pulse calcitriol in men with rising PSA after definitive treatment for prostate cancer. The primary end point will be PSA decline and PSA slope. Secondary end points will include time to progression and quality of life. The study will also closely monitor for possibly adverse effects of prolonged pulse calcitriol therapy. If pulse calcitriol proves efficacious with early metastatic prostate cancer, future studies will examine its usefulness in advanced metastatic prostate cancer and in other malignancies as well as examine promising combinations of pulse calcitriol with other agents with activity against prostate cancer.