Abstract
BACKGROUND
Preclinical and clinical data have suggested that high‐dose calcitriol (1,25‐dihydroxycholecalciferol) has activity against prostate carcinoma. Pulse‐dosed calcitriol and dexamethasone may maximize tolerability and efficacy. The authors examined the toxicity of pulse‐dosed calcitriol with zoledronate and with the addition of dexamethasone at the time of disease progression.
METHODS
Patients with progressive prostate carcinoma were eligible for the current study. In cohorts of 3–6 patients, calcitriol was administered for 3 consecutive days per week, starting at a dose of 4 μg per day. Doses were escalated to 30 μg per day. Intravenous zoledronate (4 mg) was administered monthly. Dexamethasone could be added to the regimen at disease progression. Toxicities, markers of bone turnover, plasma calcitriol levels, and clinical outcomes were recorded.
RESULTS
Thirty‐one patients were treated in cohorts that were defined by the calcitriol dose administered (4, 6, 8, 10, 14, 20, 24, or 30 μg). Seven patients received dexamethasone. Three patients had their doses reduced due to calcium‐related laboratory findings. Patients tolerated therapy well, even in the 30 μg cohort; therefore, a maximum tolerated dose was not defined. Peak plasma levels observed in the 24 μg and 30 μg cohorts ranged from 391 to 968 pg/mL. Minimal antitumor effects were observed.
CONCLUSIONS
Calcitriol was well tolerated at doses up to and including 30 μg 3 times per week in combination with intravenous zoledronate 4 mg monthly, with or without dexamethasone, in patients with progressive prostate carcinoma. Peak plasma levels in the 24 μg and 30 μg cohorts were greater than the levels associated with antitumor effects preclinically. Due to the cumbersome dosing schedule and the lack of significant activity observed, Phase II trials of this regimen are not planned. Cancer 2004. © 2004 American Cancer Society.