A phase I trial of pulse calcitriol in patients with refractory malignancies - Pulse dosing permits substantial dose escalation

BACKGROUND. Calcitriol is the principal biologically active metabolite of v itamin D. Calcitriol's activity against many neoplasms is well documented, but calcitriol's therapeutic application has been hampered by predictable h ypercalcemia when it is given daily. Because laboratory data has suggested that intermittent exposure to high levels of calcitriol may be sufficient t o produce antiproliferative effects, the authors developed a Phase I trial to determine the maximal tolerated dose, dose-limiting toxicity, and the ph armacokinetic profile of calcitriol given weekly by mouth. METHODS. Patients with refractory malignancies were enrolled for 4 weeks of treatment followed by 4 weeks of observation. Reenrollment at a higher dos e level was permitted for patients who had evidence of response or stable d isease and no Grade 3 or greater toxicity. The starting dose was 0.06 mug/k g. RESULTS. Fifteen patients received 20 cycles of therapy. Doses up to 2.8 mu g/kg of calcitriol weekly produced no dose-limiting toxicity. While peak le vels and the area under the serum concentration-time curve of calcitriol in creased in a linear fashion at lower doses, saturable absorption was observ ed at doses above 0.48 mug/kg. Doses of 0.48 mug/kg and above produced mean peak calcitriol levels of 1625 pg/mL, approximately 25-fold greater than t op normal levels and well within the therapeutic range suggested by in vitr o experiments. Eight patients experienced self-limiting Grade 1 hypercalcem ia. CONCLUSIONS. Weekly dosing of oral calcitriol permitted substantial dose es calation with minimal toxicity. Peak serum calcitriol levels were in the pr edicted therapeutic range. A dose of 0.5 mug/kg was selected for evaluation in Phase II studies. (C) 2001 American Cancer Society.