Phase I study of weekly DN-101, a new formulation of calcitriol, in patients with cancer

DN-101 is a new, high-dose, oral formulation of calcitriol under investigation for the treatment of cancer. We sought to evaluate the tolerability and pharmacokinetics (PK) of weekly doses of DN-101 in patients with advanced cancer. Patients who completed a previously reported single dose escalation study of DN-101 [Beer et al. (2005) Clin Cancer Res 11:7794-7799] were eligible for this continuation weekly dosing study. Cohorts of 3-10 patients were treated at doses of 15, 30, 45, 60, and 75 mu g calcitriol. Once 45 mu g was established as the maximum tolerated dose (MTD), this cohort was expanded to include 18 patients. Dose limiting toxicity (DLT) was defined as >= grade 2 hypercalcemia or >= grade 3 persistent treatment-related toxicities. Thirty-seven patients were recruited. DLT of transient reversible grade 2 hypercalcemia (serum calcium of 11.6-12.5 mg/dL) occurred in two of six patients treated with 60 mu g of DN-101. No DLT was observed in the 18 patients who received DN-101 weekly at 45 mu g. Overall, DN-101 was well tolerated. The most frequent adverse events were fatigue (27%), hypercalcemia (19%, including five grade 1, two grade 2, and no grade 3 or 4 events), and grade 1 nausea (16%). PK parameters following repeat dosing were comparable to those for the initial dose (n = 4). The MTD for weekly DN-101 was established as 45 mu g. The DLTs observed were two episodes of rapidly reversible grade 2 hypercalcemia in two of the six patients treated at 60 mu g weekly. Repeat doses of DN-101 at 45 mu g weekly are well tolerated and this dose is suitable for studies of weekly DN-101 in cancer patients.