Page 250 - Vitamin D and Cancer

10 Vitamin D and Prostate Cancer 237

Building on the pre-clinical evidence of synergy with taxanes, the next effort
involved combining weekly calcitriol with docetaxel. Chemotherapy-naïve
metastatic androgen-independent prostate cancer patients received oral calcitriol
2
0.5 mg/kg on day 1, followed by docetaxel 36 mg/m intravenously on day 2 weekly
for 6 consecutive weeks, repeated every 8 weeks in a phase II single institution
clinical trial [139]. Of the 37 patients, 81% had a confirmed PSA response, while
toxicity was similar to what would be expected with docetaxel alone. RECIST
criteria for response was met in 53% of the 15 patients with measurable disease.
The median overall survival was 19.5 months. These results were quite encouraging
when contrasted with contemporary results seen with docetaxel alone and stimu-
lated the development of a larger effort.
ASCENT (AIPC Study of Calcitriol Enhancing Taxotere) was launched to more
robustly examine the possibility that weekly calcitriol enhances the activity of
weekly docetaxel. This placebo-controlled international multi-institutional random-
ized study that compared weekly DN-101 + docetaxel to placebo + docetaxel in 250
patients with chemotherapy-naïve AIPC enrolled at 48 sites in the US and Canada.
For 3 consecutive weeks out of 4, 45 mg of DN-101 was given 24 hours before
docetaxel 36 mg/m . Although the study did not meet its primary endpoint of PSA
2
response rate improvement, the observed trend favored the experimental arm with
an overall PSA response rate of 63% compared to 52%, p = 0.07. Overall survival,
a secondary endpoint, was better in the experimental arm than in the docetaxel arm
(HR 0.67, p = 0.035). Interestingly, calcitriol did not appear to add toxicity to doc-
etaxel and exploratory analyses suggested a lower incidence of thrombotic and
gastrointestinal toxicity in the experimental arm. The overall results of ASCENT
were thought to be sufficiently encouraging to warrant a phase III program [140].
The 3 days out of 7 schedule was also examined further in a phase II study with
dexamethasone [141]. In this study, calcitriol was given at 8–12 mg/day for 3 con-
secutive days repeated every week. Four milligrams of dexamethasone was given
for 4 of every 7 days. Nineteen percent of the 37 patients enrolled had a PSA
response and treatment was well tolerated. While encouraging, this response rate is
difficult to interpret with confidence because the activity of this dose and schedule
of dexamethasone is not known (Table 10.6).

Less Frequent Dosing

A dose de-escalation study of 60 mg of calcitriol was administered to AIPC patients
every 3 weeks 24 hours before chemotherapy with docetaxel and estramustine
[142]. Although this study was not designed to test efficacy, responses were seen in
55% of chemotherapy naïve patients and 9% of patients previously treated with
docetaxel-containing chemotherapy, while at the same time showing that 60 mg of
calcitriol can be safely administered.
Calcitriol 0.5 mg/kg dosed every 4 weeks was evaluated in combination with
carboplatin dosed at AUC of 7 (6 in patients with prior radiation) in a small phase
II study of patients with AIPC [143]. Seventeen patients had a response rate of less