Phase I/II Study of 19-nor-1α-25-Dihydroxyvitamin D2 (Paricalcitol) in Advanced, Androgen-Insensitive Prostate Cancer

Abstract

Purpose: We assessed the safety and efficacy of the vitamin D analogue, 19-nor-1a-25-dihydroxyvitamin D 2 (paricalcitol), in patients with androgen-independent prostate cancer. Experimental Design: Patients received paricalcitol i.v. three times per week on an escalating dose of 5 to 25 Ag (3-15 Ag/m 2 ). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were characterization of toxicity in this population, changes in serum parathyroid hormone (PTH), and survival. Results: A total of 18 patients were enrolled. No patient showed a sustained 50% drop in serum PSA, despite several large declines in PSA (e.g., 1,300 ng/mL). Paricalcitol was well tolerated. One instance of significant hypercalcemia, a serum calcium of 14.3 mg/dL, was observed at the highest dose (25 Ag). At entry into the study, seven (41%) of the patients had elevated serum levels of PTH, which were significantly reduced by paricalcitol. Higher levels of serum PTH at study entry were significantly and negatively associated with survival (P < 0.01). Conclusion:No objective responses were seen in the primary end point. However, elevated serum levels of PTH, a common feature of advanced prostate cancer, were reduced by paricalcitol. Because elevated PTH is associated with increased cardiovascular and skeletal morbidity, including an increased risk for pathologic fracture, further evaluation of paricalcitol in the reduction of skeletal morbidity in advanced prostate cancer is warranted. Prostate cancer is the most prevalent (nonskin) cancer amongAmerican men and the second most fatal, accounting for >30,000 deaths in 2005 (1). For men with advanced disease, the mainstay of prostate cancer therapy is androgen withdrawal. Although androgen withdrawal is usually effective in lowering prostate-specific antigen (PSA) in men with prostate cancer, in men with metastatic disease, the duration of response is brief (about 14-18 months), and androgen-independent prostate cancer (AIPC) supervenes in virtually all treated men. The median survival once AIPC develops is 12 to 18 months. Although recent clinical trials in AIPC have shown a survival benefit for docetaxel-based chemotherapy, the benefit is modest (about 2 months; refs. 2, 3). Thus, new therapies for AIPC are urgently needed (4, 5).Considerable attention has focused on the role of vitamin D in prostate cancer, stemming from the observation by Schwartz and Hanchette that mortality rates from prostate cancer are inversely related to levels of UV radiation, the major source of vitamin D (6). Vitamin D is synthesized in response to sunlight and undergoes hydroxylation in the liver to 25-hydroxyvitamin D (calcidiol) and then in the kidney to form 1,25-dihydroxyvitamin D (calcitriol), the hormonal form of vitamin D. Extensive research has shown that prostate cells, including prostate cancer cells, express specific receptors (VDR) for 1,25-dihydroxyvitamin D. When bound to the VDR, 1,25-dihydroxyvitamin D regulates >60 genes that exert prodifferentiating, antiproli...

Paricalcitol Enhances the Chemopreventive Efficacy of 5-Fluorouracil on an Intermediate-Term Model of Azoxymethane-Induced Colorectal Tumors in Rats

“…Interestingly, in comparison with their monotherapy, cotherapy with paricalcitol and 5-FU had resulted in augmenting effects in inhibiting the formation . In turn, our findings not only support the importance of paricalcitol as an adjuvant agent in cancer therapy (10,(12)(13)(14)(15)(16), but also are in harmony with the hypothesis that vitamin D or its analogues improve tumor cell sensitivity and tumoricidal efficacy of 5-FU (6, 7). Development and progression of colorectal cancer is multigenic and heterogeneous in origin, and also has clinical importance as predictors of disease prognosis and treatment response (37).…”

“…On the other hand, the potential antitumor properties of paricalcitol, a synthetic less calcemic vitamin D analogue directly activates VDR, have recently attracted a specific deal of attention (9,10,(13)(14)(15)(16). Herein, an intermediate-term (15 weeks) model of colorectal tumorigenesis was induced in rats by AOM, a commonly used in vivo model for the experimental study of human colorectal cancer at several aspects (18)(19)(20); our study was designed to investigate the chemopreventive efficacy of paricalcitol and 5-FU alone and in combination, and whether their cotherapy resulted in an enhanced chemopreventive effect than individual therapy on this model.…”

“…Among these analogues, paricalcitol (19-nor-1a-25-dihydroxyvitamin D 2 ), a direct acting VDR activator that is clinically approved by the FDA for the treatment of secondary hyperparathyroidism, has recently gained attention on a variety of disease modalities, including cancer, due to its less calcemic effects, wider therapeutic window, and an equipotential activity as calcitriol in several in vivo and in vitro systems (8)(9)(10)(11). In cancer patients, paricalcitol may have potential safety and feasibility in women with metastatic breast cancer (12), and in men with advanced prostate cancer (13). Paricalcitol has also demonstrated potential suppressive effects on a variety of human cancer cells and preclinical tumor models such as pancreatic cancer (14), gastric cancer and peritoneal metastasis (10), uterine fibroids (15), androgen-dependent prostate cancer cell model (16), and human leukemic cells (17).…”

Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment

“…Although no objective responses were seen, 30% of the patients experienced stable disease for O6 months, suggesting possible cytostatic activity (Liu et al 2003). In a phase I/II study of the calcitriol analog 19-nor-1a-25(OH)2D 2 (paricalcitol) in patients with AIPC, no PSA or objective responses were seen (Schwartz et al 2005). However, the data suggested that paricalcitol might be beneficial in the reduction of skeletal morbidity (Schwartz et al 2005).…”

“…In a phase I/II study of the calcitriol analog 19-nor-1a-25(OH)2D 2 (paricalcitol) in patients with AIPC, no PSA or objective responses were seen (Schwartz et al 2005). However, the data suggested that paricalcitol might be beneficial in the reduction of skeletal morbidity (Schwartz et al 2005). Administration of the VDR agonist elocalcitol (BXL-628) has been shown to arrest prostate growth in patients with BPH (Maggi et al 2006).…”