Phase II open label, multi-center clinical trial of modulation of intermediate endpoint biomarkers by 1α-hydroxyvitamin D2 in patients with clinically localized prostate cancer and high grade pin

Abstract

Background: Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention. Major risk factors for this disease have been associated with low serum levels of vitamin D. Here, we evaluate the biologic activity of a less calcemic vitamin D analog 1α-hydroxyvitamin D2 [1α-OH-D2] (Bone Care International, Inc.) in patients with prostate cancer and high grade prostatic intraepithelial neoplasia (HG PIN).

Methods: Patients with clinically organ-confined prostate cancer and HG PIN were randomized to 1α-OH-D2 versus placebo for 28 days prior to radical prostatectomy. Intermediate endpoint biomarkers included serum vitamin D metabolites, TGFß 1/2, free/total PSA, IGF-1, IGFBP-3, bFGF, and VEGF. Tissue endpoints included histology, MIB-1 and TUNEL staining, microvessel density and factor VIII staining, androgen receptor and PSA, vitamin D receptor expression and nuclear morphometry.

Results: The 1α-OH-D2 vitamin D analog was well tolerated and could be safely administered with good compliance and no evidence of hypercalcemia over 28 days. While serum vitamin D metabolite levels only slightly increased, evidence of biologic activity was observed with significant reductions in serum PTH levels. TGF-ß2 was the only biomarker significantly altered by vitamin D supplementation. Whether reduced TGF-ß2 levels in our study is an early indicator of response to vitamin D remains unclear.

Conclusions: While further investigation of vitamin D may be warranted based on preclinical studies, results of the present trial do not appear to justify evaluation of 1α-OH-D2 in larger clinical prostate cancer prevention studies.

Fig. 1

Studyschema.

Fig. 2

a: Serum vitamin D metabolite (ng/ml) by visit for the treatment arm. A slight increase in vitamin D metabolite on days 8 and 28 was observed which is non-significant (P 0.219 and P = 0.148 for Wilcoxon signed-rank test). b: Absolute change for plasma intact PTH by visit. Absolute changes from baseline show significant differences across the arms for each visit with P = 0.030 for day 8, P = 0.010 for day 15, P = 0.003 for day 21, and P = 0.001 for day 28. c: Absolute change from baseline for TGF-β2 (with platelet normalization), found to exhibit a lower trend for the treatment arm for day 21 (P = 0.068) and was significantly lower for day 28 (P = 0.007, P = 0.012 [LOCF]) as shown. No significant difference between arms was observed for day 15 (P = 0.318).