Phase I Safety and Pharmacodynamic of Inecalcitol, a Novel VDR Agonist with Docetaxel in Metastatic Castration-Resistant Prostate Cancer Patients

• Published in: Clinical cancer research 2014-09, Vol.20 (17), p.4471-4477
• Main Authors: MEDIONI, Jacques, DEPLANQUE, Gael, RENAUX, Stephanie, DUFOUR-LAMARTINIE, Jean-Francois, ELAIDI, Reza, LEREST, Celine, OUDARD, Stephane, FERRERO, Jean-Marc, MAURINA, Tristan, RODIER, Jean-Michel P, RAYMOND, Eric, ALLYON, Jorge, MARUANI, Gerard, HOUILLIER, Pascal, MACKENZIE, Sarah
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alkynes - administration & dosage; Alkynes - adverse effects; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Biological and medical sciences; Cholecalciferol - administration & dosage; Cholecalciferol - adverse effects; Disease Progression; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Prostate-Specific Antigen - blood; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Calcitriol - agonists; Receptors, Calcitriol - genetics; Taxoids - administration & dosage; Taxoids - adverse effects; Treatment Outcome; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-3247

We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol. Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg 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. Eight dose levels (40-8,000 μg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 μg/day after one and two 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 4,000 μg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 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. 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 II study is planned.