Page 253 - Vitamin D and Cancer

240 C.M. Barnett and T.M. Beer

10.6.3 Clinical Trials of Calcitriol Analogs in Prostate Cancer

An alternative to calcitriol, calcitriol analogs have been developed in the hope of
overcoming calcemic toxicity, while maintaining antineoplastic activity. Many
compounds have been chemically synthesized, primarily with side chain modifica-
tions. It is hoped that reduced calcemic toxicity may be a result of differences in
protein binding, VDR affinity, and drug metabolism [144–146].
After phase I studies in pancreatic and hepatocellular carcinoma, [147]
Seocalcitol (EB 1089, Leo Pharmaceuticals, Ballerup, Denmark) 10 mg entered
phase II studies. Results in unresectable hepatocellular carcinoma show that 2 of
33 evaluable patients had a complete remission enduring beyond 29 months (last
point of analysis), [148] while no responses were seen in pancreatic cancer
[149]. Another analog, topical calcipotriol, had observed responses in 3 of 14
patients with locally advanced or cutaneous metastatic adenocarcinoma of the
breast [150].
In a phase I study of 1-alpha-hydroxyvitamin D [151] 12.5 mg was identified as
2
the safe dose due to dose limiting hypercalcemia and renal insufficiency. Two of 25
androgen independent prostate cancer patients had objective responses, which lead
to the development of a phase II study. In this follow-up study, 26 patients were
enrolled to evaluate progression free survival. One patient had stable disease for
more than 2 years, while the median time to progression was 12 weeks (mean
19 weeks). In a randomized phase II study, 70 chemotherapy-naïve men with AIPC
were treated with weekly docetaxel with or without 1-alpha-hydroxyvitamin D
2
given at a dose of 10 mg/day. The response rates, time to disease progression, and
toxicity were similar in both arms of the study [152].
Another analog, ILX23–7553, was evaluated in a phase I clinical trial. It was
2
found that doses up to 45 mg/m /day for 5 consecutive days repeated every 14 days
was safe, but the number of capsules required prompted early closure. The authors
conclude that a reformulation at a higher dose may be a more feasible study in the
future [153].
19-Nor-1alpha-25-dihydroxyvitamin D2 (paricalcitol) was examined in a phase I
study in 18 patients with androgen-independent prostate cancer. Paricalcitol was
given i.v. three times per week with doses between 5 and 25 mg tested [154]. While
some PSA declines were seen, no patient had a sustained PSA response. One epi-
sode of hypercalcemia was noted at the highest dose tested. Interestingly, serum
parathyroid hormone levels, elevated at study entry in 41% of patients, were
reduced with therapy.
Vitamin D remains an exciting area of investigation in prostate cancer epidemi-
ology, prevention, and therapy. Despite compelling biology and supportive epide-
miology, to date, definitive results have not been reported. There are sufficient data
to expect that with further work, a role for vitamin D in reducing the risk of prostate
cancer diagnosis and death, as well as improved outcomes in prostate cancer treat-
ment will be identified. It is tempting to consider that human biologic heterogeneity
in vitamin D sensitivity has not been fully considered in the studies conducted to