DN-101 may protect against major side effects of chemotherapy

Nov 3 2005

Men with advanced prostate cancer who take an experimental, high-dose vitamin D pill with chemotherapy live about eight months longer than those receiving chemotherapy and placebo, according to a new study.

The pill is DN-101. Designed specifically as a cancer therapy, it is a unique form of calcitriol, a naturally occurring hormone and the biologically active form of vitamin D. Research also shows that DN-101 may protect against major side effects of chemotherapy.

"When DN-101 is added to chemotherapy, it provides a significant improvement in survival for advanced prostate cancer patients," said Tomasz Beer, M.D., national leader of the clinical trial and director of the Prostate Cancer Program in the Oregon Health & Science University Cancer Institute. "DN-101 extends lives and it may also protect against side effects of chemotherapy, providing a kind of one-two punch in cancer therapy."

Beer presented results from the AIPC Study of Calcitriol Enhancing Taxotere (ASCENT) on Wednesday, Nov. 2, at the 13th annual meeting of the European Cancer Conference (ECCO) in Paris. Christopher Ryan, M.D, member of the OHSU Cancer Institute, served as principal investigator at the OHSU study site.

ASCENT is a randomized, double-blinded, placebo-controlled clinical trial to evaluate DN-101 given with docetaxel (Taxotere) for advanced prostate cancer research subjects who are no longer responding to hormonal therapy, a condition known as androgen-independent prostate cancer (AIPC). Two hundred, fifty subjects participated in the study at 48 sites between September 2002 and January 2004.

The estimated survival of subjects receiving DN-101 with docetaxel is 24.5 months. Those receiving placebo with docetaxel had a median survival of 16.4 months.

"We have not yet reached an observed median survival in the DN-101 study arm for a very good reason," Beer said. "More than half of these subjects are still living, which is very good news."

Subjects taking DN-101 with docetaxel have a 49 percent increase in survival. This benefit was statistically significant (p=0.035) with a hazard ratio of 0.67.

DN-101 also appears to protect against side effects of chemotherapy. In an exploratory analysis of safety data, researchers found that serious adverse events, primarily those requiring hospitalization, occurred in 28 percent of subjects taking DN-101 with docetaxel compared to 41 percent of subjects receiving placebo and docetaxel. This difference was statistically significant. Subjects in the DN-101 study arm experienced fewer gastrointestinal and thromboembolic events.

"This is both surprising and pleasing," Beer said. "A cancer treatment that improves survival and decreases toxicity is exceedingly rare."

Overall survival was a secondary endpoint. ASCENT's primary endpoint was a 50 percent or more reduction of prostate specific antigen (PSA), a protein made only by prostate cells. Certain prostate conditions, including prostate cancer, are associated with high levels of PSA in the blood.

Overall PSA responses occurred more frequently in subjects receiving DN-101 plus docetaxel (63 percent) versus docetaxel alone (52 percent). While the difference between the two arms did not reach statistical significance (p=0.07), the combination results represent an historically strong PSA response.

"During the past year, new work done by colleagues in the field has shown that only about half of survival can be explained by changes in PSA," Beer said. "Though PSA remains important, it has turned out to be a middle-of-the-road predictor of survival."

DN-101 works by producing much higher blood levels of calcitriol than the body can produce from dietary vitamin D or vitamin D supplements. In high doses, it enhances many commonly used chemotherapeutic agents, producing anti-tumor activity in laboratory and animal models. ASCENT was designed to confirm results from a small, phase II OHSU study led by Beer that showed dramatic PSA reductions in subjects who took high doses of calcitriol with chemotherapy. In the phase II study, subjects were taking as many as several hundred pills within a few hours to achieve the right concentration of calcitriol. Beer and former OHSU faculty member W. David Henner, M.D., invented a technology to develop a highly concentrated form of the vitamin.

OHSU licensed this technology to Novacea Inc., the company formed to develop DN-101. Henner, a former OHSU faculty member, has since joined Novacea to play a key role in the development of the drug. ASCENT was sponsored by Novacea, maker of DN-101, with support from Sanofi-Aventis, maker of Taxotere.

Based on ASCENT results, Novacea plans to begin a phase III clinical trial in early 2006.

Beer and OHSU have a significant financial interest in Novacea, a company that may have a commercial interest in the results of this research and technology. This potential conflict was reviewed and a management plan approved by the OHSU Conflict of Interest in Research Committee, and the Integrity Program Oversight Council was implemented.