Docetaxel/Calcitriol in Androgen-Independent Prostate Cancer

February 1, 2003

NEW YORK-In patients with androgen-independent prostate cancer, a pulsed regimen of docetaxel (Taxotere) plus high-dose calcitriol is well tolerated and results in disease response by a variety of standard measures, according to results of a phase II trial.

NEW YORK—In patients with androgen-independent prostate cancer, a pulsed regimen of docetaxel (Taxotere) plus high-dose calcitriol is well tolerated and results in disease response by a variety of standard measures, according to results of a phase II trial.

"The combination is promising in androgen-independent prostate cancer as measured by PSA response rate, measurable disease response rate, time to progression, and overall survival," said investigator Tomasz M. Beer, MD, assistant professor of medicine, Oregon Health & Science University.

With the possible exception of an increase in gastrointestinal side effects, the toxicity profile was not different than what would be expected with docetaxel alone; furthermore, the two agents do not appear to alter each other’s pharmacokinetic profiles, said Dr. Beer, who presented the data at the Mount Sinai School of Medicine Chemotherapy Foundation Symposium XX.

The findings are the latest to suggest a potential role in prostate cancer for calcitriol, the biologically active form of vitamin D. Preclinically, calcitriol has been shown to downregulate apoptosis inhibitors, induce cell cycle arrest and differentiation, and inhibit proliferation of multiple prostate cancer cell lines, including PC-3 and LNCaP.

In these cell lines, calcitriol at concentrations of 0.01 nM (approximating endogenous calcitriol concentrations) did not significantly inhibit growth. However, in concentrations of 1 nM and higher, there was a significant and dose-dependent inhibition of both cell lines, said Dr. Beer, describing results that came from his group’s laboratory but that are similar to those reported by others.

These preclinical studies have also suggested synergy with several cytotoxic agents, providing a rationale for the clinical trial of the calcitriol/docetaxel combination. For example, Dr. Beer said, in PC-3 cells incubated with either calcitriol or docetaxel, colony formation is about 60% of what is seen in controls; in cells incubated with both agents, colony formation is about 20% of control levels.

The major barrier to clinical application of these findings has been hypercalcemia at calcitriol doses high enough to result in antitumor activity. Development of high-dose calcitriol compounds that produce transient high plasma levels of calcitriol when given weekly (high-dose pulse administration or HDPA) has made such studies possible.

Dr. Beer and his colleagues have already presented some clinical data suggesting the promise of this combination. They treated 22 chemotherapy-naïve patients with a high-dose formulation of calcitriol, given orally once weekly, in combination with docetaxel, also given weekly. At a median of 10 months’ treatment, investigators observed no grade 3-4 toxicity, and had three confirmed PSA reductions (47%, 28%, and 10%) and significant prolongation of PSA doubling time in three patients (Cancer, in press).

"This suggests there may be some activity, but it is important to know that neither sub-50% PSA reductions nor PSA doubling time lengthening have been validated as endpoints of prostate cancer," Dr. Beer said.

Phase II Study

At this symposium, Dr. Beer presented new data from a single-center phase II investigation of calcitriol/docetaxel in 37 patients with metastatic, androgen-independent prostate cancer who had no prior chemotherapy. Median age of the patients was 72 years, and median ECOG performance status was 1. Median PSA was 99 ng/mL.

Treatment included weekly cycles of high-dose oral calcitriol (Rocaltrol, Roche Laboratories) given at a dose of 0.5 µg/kg on day 1, followed by docetaxel 36 mg/m2 intravenously over 15 to 30 minutes on day 2 (with dexamethasone pretreatment). This was repeated for 6 consecutive weeks in 8-week cycles.

With median follow-up of 17 months, grade 3-4 leukopenia and neutropenia were seen in 41% and 24%, respectively, while grade 3-4 hyperglycemia was seen in 24%. Peptic ulcers developed in 11% of patients, which "seems a bit higher than what we would have expected from docetaxel alone," Dr. Beer said.

PSA Response Rate

Activity of the regimen included an 81% PSA response rate. By comparison, PSA response in four previous trials of docetaxel alone in androgen-independent prostate cancer ranged from 35% to 46%, Dr. Beer said. PSA response is 42% if data on all 138 patients from those four trials are combined.

Fifteen patients (53%) had a measurable disease response. Time to progression was a median of 11.4 months, and overall survival was a median of 19.5 months, both of which compare favorably with historical controls (see Table), Dr. Beer said. Two of the four docetaxel-alone trials reported median time to progression of 5.1 and 4.6 months, and median overall survival of 9.4 and 9 months.

The investigators also performed an exploratory pharmacokinetic study to analyze the effect of each drug on the other. "No pharmacokinetic parameters were affected by the presence of the other agent," Dr. Beer said.

Investigators are looking for confirmation of these results in a larger, randomized, placebo-controlled phase III trial of docetaxel plus another high-dose calcitriol formulation (DN-101, Nova-cea) vs docetaxel plus placebo. This calcitriol formulation is being developed for a variety of solid tumors and hematologic malignancies.