A phase I and pharmacokinetics study of intravenous calcitriol in combination with oral dexamethasone and gefitinib in patients with advanced solid tumors.

Purpose: The primary objective of this study was to determine the maximum tolerated dose (MTD) of intravenously (i.v.) calcitriol administered in combination with a fixed oral dose of dexamethasone and gefitinib in patients with refractory solid tumors.

Methods: A fixed oral dose of dexamethasone of 4 mg/day was given every 12 h x 3 doses starting 12 h prior to i.v. calcitriol administration. Calcitriol was administered i.v. over 1 h on weeks 1, 3, and weekly thereafter. The starting calcitriol dose level was 57 microg and escalation occurred in cohorts of three patients until the MTD was defined. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Serum calcitriol PK studies were performed on day 1 (calcitriol + dexamethasone) and on day 15 (calcitriol + dexamethasone + gefitinib).

Results: A total of 20 patients were treated. Dose-limiting hypercalcemia was observed in two out of the four patients receiving 163 mcg/week of calcitriol. Mean (+/-SE) peak serum calcitriol concentration (C (max)) at the MTD (125 microg/week calcitriol) was 11.17 +/- 2.62 ng/ml and the systemic exposure (AUC(0-72 h)) of 53.30 +/- 10.49 ng h/ml. The relationship between calcitriol dose and either C (max) or AUC was linear over the 57-163 microg dose range.

Conclusions: The addition of a low dose of dexamethasone allowed the safe escalation of calcitriol to the MTD of 125 microg/week. This dose level resulted in serum calcitriol concentrations that are associated with pre-clinical antitumor activity. However, no antitumor activity was noted clinically in patients with solid tumors.