Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Jacques Medioni, Gael Deplanque, Jean-Marc Ferrero, Tristan Maurina, Jean-Michel P Rodier, Eric Raymond, Jorge Allyon, Gerard Maruani, Pascal Houillier, Sarah Mackenzie, Stephanie Renaux, Jean-Francois Dufour-Lamartinie, Reza Elaidi, Celine Lerest, Stephane Oudard
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 17 Pg. 4471-7 (Sep 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25013124 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Alkynes
• Receptors, Calcitriol
• Taxoids
• VDR protein, human
• inecalcitol
• Docetaxel
• Cholecalciferol
• Prostate-Specific Antigen

Topics

• Aged
• Aged, 80 and over
• Alkynes (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Cholecalciferol (administration & dosage, adverse effects)
• Disease Progression
• Docetaxel
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis
• Prostate-Specific Antigen (blood)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Receptors, Calcitriol (agonists, genetics)
• Taxoids (administration & dosage, adverse effects)
• Treatment Outcome