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A Phase I trial of pulse calcitriol in patients with refractory malignancies
Author(s) -
Beer Tomasz M.,
Munar Myrna,
Henner W. David
Publication year - 2001
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(20010615)91:12<2431::aid-cncr1278>3.0.co;2-3
Subject(s) - calcitriol , medicine , toxicity , dosing , pharmacokinetics , refractory (planetary science) , chemotherapy , pharmacology , urology , dose–response relationship , metabolite , gastroenterology , vitamin d and neurology , endocrinology , physics , astrobiology
BACKGROUND Calcitriol is the principal biologically active metabolite of vitamin D. Calcitriol's activity against many neoplasms is well documented, but calcitriol's therapeutic application has been hampered by predictable hypercalcemia when it is given daily. Because laboratory data has suggested that intermittent exposure to high levels of calcitriol may be sufficient to produce antiproliferative effects, the authors developed a Phase I trial to determine the maximal tolerated dose, dose‐limiting toxicity, and the pharmacokinetic 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 dose level was permitted for patients who had evidence of response or stable disease and no Grade 3 or greater toxicity. The starting dose was 0.06 μg/kg. RESULTS Fifteen patients received 20 cycles of therapy. Doses up to 2.8 μg/kg of calcitriol weekly produced no dose‐limiting toxicity. While peak levels and the area under the serum concentration‐time curve of calcitriol increased in a linear fashion at lower doses, saturable absorption was observed at doses above 0.48 μg/kg. Doses of 0.48 μg/kg and above produced mean peak calcitriol levels of 1625 pg/mL, approximately 25‐fold greater than top normal levels and well within the therapeutic range suggested by in vitro experiments. Eight patients experienced self‐limiting Grade 1 hypercalcemia. CONCLUSIONS Weekly dosing of oral calcitriol permitted substantial dose escalation with minimal toxicity. Peak serum calcitriol levels were in the predicted therapeutic range. A dose of 0.5 μg/kg was selected for evaluation in Phase II studies. Cancer 2001;91:2431–9. © 2001 American Cancer Society.