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

Background: 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. Methods: 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 μg calcitriol. Once 45 μg 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. Results: 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 μg of DN-101. No DLT was observed in the 18 patients who received DN-101 weekly at 45 μg. 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). Conclusion: The MTD for weekly DN-101 was established as 45 μg. The DLTs observed were two episodes of rapidly reversible grade 2 hypercalcemia in two of the six patients treated at 60 μg weekly. Repeat doses of DN-101 at 45 μg weekly are well tolerated and this dose is suitable for studies of weekly DN-101 in cancer patients.