Anticancer agent seocalcitol

Vitamin D regulates the uptake of calcium from the diet. However, it can also regulate the proliferation and differentiation of a variety of cells, including malignant cancer cells.

But vitamin D itself causes hypercalcaemia when given in large doses, so a vitamin D analogue that has the regulatory effect, without the calcium regulating properties, could have potential as an anticancer agent. The structure of the vitamin D receptor has recently been elucidated, and provides a way in to the rational design of better agonists. Leo Pharmaceuticals has pinpointed the drug candidate seocalcitol (EB1089), which has been shown to have a strong inhibitory effect on cell proliferation, but is considerably less calcaemic than the natural hormone.¹

A Phase I study was carried out to evaluate the calcaemic effects of seocalcitol on patients with advanced cancer.² A total of 36 patients with advanced breast or colorectal cancer were given between 0.15 and 17µg/m² of seocalcitol a day. It was well tolerated with few adverse events, and the dose estimated to be tolerable for most patients in the study was around 7µg/m² a day.

Patients with inoperable pancreatic cancer were given the drug in a Phase II trial.³ Once daily oral seocalcitol was given to 36 patients with advanced pancreatic cancer, with dose escalation every two weeks until hypercalcaemia occurred; at this point, the patients continued with maintenance therapy. Most patients tolerated a dose of 10-15µg/day in chronic administration. It was well tolerated, with the most frequent problem being the anticipated dose-dependent hypercalcaemia. However, further studies are required to determine if the drug has cytostatic activity in earlier stage pancreatic cancer.

Two prospective, multi-centre, randomised placebo-controlled Phase III trials of the drug in hepatic cancer are currently under way, one using seocalcitol as monotherapy and the second as an adjuvant treatment.