Dose-finding and efficacy phase II study of inecalcitol, a new VDR agonist, in combination with docetaxel-prednisone regimen for castration-resistant prostate cancer (CRPC) patients (pts).

Abstract

142 Background: Inecalcitol is a novel vitamin D receptor (VDR) agonist which shows high antiproliferative effects in human cancer cell lines and a 100-fold lower hypercalcemic activity than calcitriol the natural ligand of VDR. Methods: Escalating dosages of inecalcitol were combined to chemotherapy in naive metastatic CRPC patients. Safety and efficacy were evaluated in groups of 3-6 pts receiving inecalcitol every other day, daily or twice a day on a 21-day cycle in combination with docetaxel (75mg/m2 q3w) and oral prednisone (5mg bid). Pts received up to six cycles unless unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) defined as G3 hypercalcemia within the first cycle. Efficacy endpoint was PSA response defined as ≥30% decline within 3 months. Results: Eight dose levels from 40 to 8,000 μg have been evaluated in 54 pts; 83 % had bone metastases, 13% had visceral disease only. Median age was 71 years (range, 49-87), median Gleason score (Gs) 7 and median PSA 28.5 ng/mL (range, 0.8-962.4). DLT occurred in 2/4 patients receiving 8,000 μg/day after 1 and 2 weeks of treatment. Calcemia normalized in few days after interruption of treatment. The 2 other experienced only G2 and were stepped down to 4,000 μg. After dose reduction, calcemia remained within normal ranges and G1.The maximum tolerated dose is defined at 4,000 μg qd. Most of adverse events reported were grade 2. G3-4 were mainly hematological toxicity. Frequency of AEs related to docetaxel did not seem to be modified.82% of the patients had ≥30% PSA decline within 3 months of treatment whereas in historical data around 65% are responder with docetaxel as a single agent. PSA response was observed after 1 cycle of treatment in 43% of the patients. Time to biochemical relapse defined as an increase of 25% over nadir was 169 days. Conclusions: High antiproliferative daily dose of inecalcitol, a new VDR, agonist has been safely used in combination with docetaxel in CRPC patients. This combination treatment shows encouraging PSA response (> 30% PSA response: 82%). A multicenter randomized double blind phase III study is forecasted to confirm these results. [Table: see text]