Page 252 - Vitamin D and Cancer

10 Vitamin D and Prostate Cancer 239

than 10% with unremarkable toxicity. It is unclear if the infrequent dosing or the
platinum resistance of prostate cancer had an impact on these results.
Nineteen patients with metastatic AIPC received DN-101 180 mg p.o. on day 1
2
and mitoxantrone 12 mg/m i.v. on day 2 every 21 days with continuous daily
prednisone 10 mg p.o. for a maximum of 12 cycles. This trial examined the high-
est dose of calcitriol evaluated in a phase II study, but used an infrequent dosing
schedule. Five of 19 patients (26%; 95 CI 9%–51%) achieved a PSA decline and
47% (95% CI 21%–73%) achieved an analgesic response (BJU International, in
press).
Overall, the phase II studies of infrequently given high dose calcitriol, even
using very high doses, did not produce remarkable results, suggesting that weekly
dosing maybe a more promising strategy.

10.6.2.4 Phase III Studies

With encouraging results from the ASCENT study in hand, Novacea, Inc. pursued
phase III development of DN-101. The ASCENT-2 study sought to determine if
the addition of DN-101 to docetaxel improved overall survival. The design of this
study faced several important challenges. While much of the high dose calcitriol
program, and the encouraging results from the ASCENT study were derived from
a program of weekly administration of high dose calcitriol along with weekly
chemotherapy, a 3-weekly regimen of docetaxel and prednisone had become the
2
standard of care. Tannock et al. reported that docetaxel 75 mg/m with low dose
daily prednisone improve the overall survival of AIPC patients over the prior
standard of mitoxantrone and prednisone. At the same time, a weekly regimen of
30 mg/m administered for 5 of every 6 weeks, designed to be equal in dose
2
intensity to the 3-weekly arm, but distinct from all previously studies weekly
regimens of docetaxel in prostate cancer, did not produce a survival
improvement.
The phase III program, with the primary endpoint of survival, compared the
winning arm of ASCENT that consisted of 45 mg of DN-101 + docetaxel at
2
36 mg/m weekly for 3 of every 4 weeks to the FDA approved standard of doc-
2
etaxel 75 mg/m with daily prednisone. This large study was halted early due to
excess deaths in the experimental arm. Recently, the Food and Drug Administration
lifted the resulting hold on studies of DN-101. This disappointing result is diffi-
cult to interpret due to the multiple differences between the two arms of the study.
In addition to the presence or absence of high dose calcitriol, the two arms differ
with respect to: (1) the dose and schedule of docetaxel, (2) the dose intensity of
docetaxel, (3) the use of prednisone, and (4) the dose and schedule of dexametha-
sone. Thus, this unblinded study did not directly examine the contribution of high
dose calcitriol to the safety and efficacy of chemotherapy. Rather, it was designed
to meet the regulatory requirements for drug approval. The failure of this study
leaves us uncertain about the potential of high dose calcitriol as a useful cancer
treatment.