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

4605 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 patients 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). Patients 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; 87 % had bone metastases, 13% had visceral disease only. Median age was 71 years [range, 49-87], median Gleason score (Gs) 7 and mean PSA 75 ng/mL±146.92. 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. 85% and 76% of the patients had ≥30% PSA decline within 3 months of treatment and ≥50% PSA decline any time on study respectively. Historical data published with docetaxel as a single agent showed 67% and 48% of responder respectively. PSA decline ≥30% was observed after 1 cycle of treatment in 43% of the treated patients.


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: 85% - (> 50% PSA response: 76%). A multicenter randomized double blind phase III study is forecasted to confirm these results.