Page 248 - Vitamin D and Cancer

10 Vitamin D and Prostate Cancer 235

(AIPC) [135]. PSA response was noted in 38% of patients. The interpretation of this
result is challenging because both dexamethasone and carboplatin have some activ-
ity in prostate cancer. Nonetheless, the response rate is respectable.

Dosing 3 of Every 7 Days

Dosing calcitriol for 3 consecutive days, every 7 days was evaluated in two studies
in combination with other drugs. The first trial was a phase I combination with
paclitaxel, with daily doses up to 38 mg on three consecutive days. C max ranges of
1.4–3.5 nM at the highest doses did not produce dose limiting toxicity [131]. The
second study was in combination with zoledronate with dexamethasone added upon
progression [136]. Calcitriol was administered on the same schedule as it was on
the previous study at doses of 30 mg. While there were not dose limiting toxicities,
three patients did have dose reductions due to laboratory abnormalities. The only
patient responses to this regimen were observed when dexamethasone was added
upon patient progression.

Intravenous Calcitriol

Having observed an absorption-related pharmacokinetic ceiling, the Roswell Park
group examined weekly intravenous calcitriol in a phase I study that included
patients with a range of solid tumors [137]. In this study, gefitinib was given as the
partner drug. Dose limiting hypercalcemia was reached in two patients who were
receiving 96 mg of calcitriol/week (Table 10.5).
In a series of studies, intermittent dosing has been shown to result in significant
dose escalation. A novel formulation, DN-101 circumvented the previously
described non-linear pharmacokinetics, and in doing so provided evidence that the
phenomenon is likely to be related to the formulation rather than the parent com-
pound. DN-101 also allowed for much more convenient dosing that required one or
several capsules instead of dozens if not more than 100. As a result, the develop-
ment of DN-101 allowed large scale trials of high dose calcitriol.

10.6.2.3 Phase II Studies

Weekly Dosing

Patients who had a biochemical progression after prostatectomy or radiation
therapy were enrolled in a non-randomized study of weekly calcitriol of 0.5 mg/kg
[138]. Patients were treated for a median of 10 months demonstrating the long-term
safety of this approach. Lengthening of the PSA doubling time when compared to
pre-treatment and a handful of minor PSA reductions with treatment were seen.
Absent a control arm, it would be difficult to be certain whether these observations
indicate true anti-tumor activity.