© 2008 THE AUTHORS JOURNAL COMPILATION © 2 0 0 8 B J U I N T E R N A T I O N A L | 1 0 2 , 1 6 0 1 – 1 6 0 6 | doi:10.1111/j.1464-410X.2008.08017.x 1601 2008 THE AUTHORS. JOURNAL COMPILATION 2008 BJU INTERNATIONAL Urological Oncology DN-101 WITH MITOXANTRONE AND PREDNISONE IN AIPC CHAN et al. A phase II study of high-dose calcitriol combined with mitoxantrone and prednisone for androgen-independent prostate cancer Joseph S. Chan, Tomasz M. Beer, David I. Quinn*, Jacek K. Pinski*, Mark Garzotto, Mitchell Sokoloff, Daniel R. Dehaze and Christopher W. Ryan Oregon Health & Science University, Portland, OR, and *Kenneth J. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Accepted for publication 15 May 2008 day 2 every 21 days with continuous daily prednisone 10 mg orally for a maximum of 12 cycles. A confirmed decline in prostate- specific antigen (PSA) levels by half was the primary endpoint. QoL was evaluated using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire, and pain and analgesic use were evaluated. RESULTS Five of 19 patients (26%; 95% confidence interval, CI, 9–51) achieved a ≥ 50% decline in PSA level. The median (95% CI) time to PSA progression was 16 (6–26) weeks. The overall median (95% CI) survival was 16 (6–26) months; 47 (21–73)% of patients achieved an analgesic response. Toxicity was similar to that expected with mitoxantrone and prednisone alone. The QoL analysis suggested a decrease in physical functioning and increase in fatigue, insomnia, and diarrhoea. CONCLUSIONS DN-101 given every 3 weeks does not add significant activity to mitoxantrone and prednisone in AIPC, as measured by the PSA decline. The high rate of analgesic response is encouraging. The addition of DN-101 does not appear to increase the toxicity of mitoxantrone. KEYWORDS DN-101, calcitriol, mitoxantrone, prostate cancer Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE To evaluate the preliminary efficacy, safety, and impact on quality of life (QoL) of high- dose calcitriol (DN-101) combined with mitoxantrone and glucocorticoids in androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS Nineteen patients with metastatic AIPC and no previous chemotherapy received DN-101 180 μ g orally on day 1 and mitoxantrone 12 mg/m 2 intravenously on INTRODUCTION Mitoxantrone plus prednisone is an established chemotherapy regimen for patients with androgen-independent prostate cancer (AIPC). Two randomized studies evaluating glucocorticoid therapy with and without mitoxantrone established the quality of life (QoL) and palliative benefit of the combination, although with no evident improvement in overall survival [1,2]. Although two subsequent randomized studies showed better survival with docetaxel-based treatment than that with mitoxantrone and prednisone, the absolute survival benefit was modest (1.9 and 2.4 months), and docetaxel was associated with higher rates of toxicity [3,4]. As mitoxantrone + prednisone is well- tolerated and with established palliative activity, potential enhancement of this regimen with noncytotoxic agents is worthy of study. Calcitriol, a potent naturally occurring hormone and the biologically active form of vitamin D, is the natural ligand for the vitamin D receptor [5]. At supraphysiological concentrations, calcitriol has antiproliferative activity in prostate cancer cell lines and in animal models of prostate cancer [6,7]. The mechanism of the anti-neoplastic activity of calcitriol remains incompletely characterized, but might be related to changes in growth factor systems, induction of apoptosis, and inhibition of angiogenesis [6,8]. Adding calcitriol to mitoxantrone and glucocorticoids synergistically inhibited growth in a PC-3 cell line and enhanced tumour regression in a mouse xenograft model [9]. DN-101 is an orally administered, high-dose formulation of calcitriol, specifically developed for cancer therapy [10]. DN-101 was studied in the ASCENT study, a randomized, placebo-controlled, phase II trial of weekly docetaxel with and without DN-101 [11]. While the primary endpoint of that study (the rate of PSA decline) was not statistically different, there was an overall survival benefit with no increment in toxicity, in the analysis of secondary endpoints. Exploratory analyses of safety suggested that adding DN-101 might result in a decrease in thromboembolic and gastrointestinal complications of chemotherapy [11]. To further investigate the clinical activity and safety of intermittent high-dose calcitriol with chemotherapy, we conducted a single- arm, open-label, phase 2 study of DN-101 BJUI BJU INTERNATIONAL