Dose finding and safety analysis of inecalcitol in combination with a docetaxel-prednisone regimen in hormone-refractory prostate cancer (HRPC) patients

Abstract

5151 Background: Inecalcitol is a novel synthetic vitamin D3 analogue with potent antiproliferative effects in human cancer cell lines and a 100-fold lower hypercalcemic activity than calcitriol in animal models. Methods: Escalating dosages of inecalcitol were combined to chemotherapy in naive HRPC patients (pts). Safety and efficacy were evaluated in groups of 3–6 patients receiving oral inecalcitol daily or every other day on a 21-day cycle in combination with docetaxel (75mg/m2 q3w) and oral prednisone (5mg bid). Biphosphonates were prohibited during the first cycle. Patients received up to six cycles unless unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Calcemia, creatininemia and CBC were assessed weekly; biochemistry, ECG and PSA every 3 weeks. Efficacy endpoint was PSA response defined as ≥30% decline within 3 months. Results: Five dose levels: 40, 80, 160, 300, 600 μg have been evaluated in 34 pts; 9 pts are still being treated at 600 μg; 25 pts have completed 6 cycles (13 bone metastases; 3 extrasqueletic metastasis, 8 bone and extrasqueletic metastases; 1 PSA-only disease). Median age was 72 years (range, 53–87), median Gleason score (Gs) 7 (36% Gs 10–8, 64% Gs 7–6) and median PSA 41.5 ng/mL (range, 0.9–962.4). No increased calcemia was reported. Most adverse events (AE) were G1–2, asthenia (19pts), constipation (14pts), diarrhea (13pts). G3–4 AEs were neutropenia (11pts) lymphopenia (9pts), asthenia (3pts), arrhythmia (2 pts), general health deterioration (2pts) and diarrhea (1pt). None of these AEs was considered related to inecalcitol. Of the 23 evaluable pts for PSA response, 20 (87%) had ≥30% PSA decline. Conclusions: Results from this ongoing study show the safe profile of inecalcitol when given daily in in HRPC pts. PSA responses with this combination are encouraging. As DLT was not reached, a higher dose of inecalcitol (1000 μg/day) will be further tested. [Table: see text]