Phase I Safety and Pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients
Mené sur 54 patients atteints d'un cancer métastatique de la prostate résistant à la castration, cet essai de phase I évalue la dose maximale tolérée et l'efficacité clinique, du point de vue de la baisse du taux de PSA à trois mois, de l'inecalcitol, un agoniste du récepteur de la vitamine D, en combinaison avec une chimiothérapie à base de docétaxel
Purpose: We conducted a Phase I multicenter trial in naïve metastatic CRPC patients with escalating inecalcitol dosages, combined to docetaxel-based chemotherapy. Inecalcitol is a novel Vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol. Experimental Design: Safety and efficacy were evaluated in groups of 3-6 patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75mg/m2 every 3 weeks) and oral prednisone (5mg twice a day) up to six cycles. Primary endpoint was dose limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was ≥30% PSA decline within 3 months. Results: Eight dose levels (40 to 8000 µg) were evaluated in 54 patients. DLT occurred in 2/4 patients receiving 8000 µg/day after 1 and 2 weeks of inecalcitol. Calcemia normalized a few days after interruption of inecalcitol. Two other patients reached grade 2 and the dose level was reduced to 4000 µg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4000 µg daily. Respectively, 85% and 76% of the patients had ≥30% PSA decline within 3 months and ≥50% PSA decline at any time during the study. Median time to PSA progression was 169 days. Conclusions: High antiproliferative daily inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (> 30% PSA response: 85%; > 50% PSA response: 76%). A randomized Phase 2 study is planned.