Phase I Trial of 1 -Hydroxyvitamin D2 in Patients with Hormone Refractory Prostate Cancer

This Phase I study of 1 -hydroxyvitamin D2, an p.o. administered vitamin D analogue, in patients with advanced hormone-refractory prostate cancer was designed to assess the toxicity, pharmacokinetic and biological markers of drug activity, and lastly tumor response data to recommend a dose for Phase II studies. 1 -Hydroxyvitamin D2 was administered daily at doses ranging from 5 to 15 g/day. Patients were monitored for toxicity and tumor response, and blood and urine samples were collected for pharmacokinetics (1 ,25-dihydroxyvitamin D2 levels) and other parameters of biological activity (bone markers, parathyroid hormone, urine calcium, and serum phosphorus levels). Twenty-five patients were enrolled. Main toxicities were hypercalcemia with associated renal insufficiency. No other significant toxicity was seen. Pharmacokinetics showed an increase in the active metabolite 1 ,25-dihydroxyvitamin D2 that reached a plateau by week 4 despite continuous drug dosing. Elevation in daily urinary calcium excretion and serum phosphorus levels was seen, whereas a decrease in serum parathyroid hormone was evident. Two patients showed evidence of a partial response, whereas 5 others achieved disease stabilization for >6 months. 1 -Hydroxyvitamin D2 was well tolerated with main toxicities being hypercalcemia and renal insufficiency. All of the toxicity was reversible with drug discontinuation. Evidence for drug activity was seen in surrogate markers, and pharmacokinetic analysis showed substantial increases in vitamin D metabolite levels among the various cohorts. Whereas the defined maximum tolerated dose was not reached, the recommended Phase II dose was 12.5 g/day given continuously.