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

  • Clin Cancer Res. 2014 Sep 1;20(17):4471-7. doi: 10.1158/1078-0432.CCR-13-3247.
Jacques Medioni  1 ,  Gael Deplanque  2 ,  Jean-Marc Ferrero  3 ,  Tristan Maurina  4 ,  Jean-Michel P Rodier  5 ,  Eric Raymond  6 ,  Jorge Allyon  7 ,  Gerard Maruani  8 ,  Pascal Houillier  9 ,  Sarah Mackenzie  10 ,  Stephanie Renaux  11 ,  Jean-Francois Dufour-Lamartinie  11 ,  Reza Elaidi  12 ,  Celine Lerest  12 ,  Stephane Oudard  13
Affiliations
  • 1. Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France. Paris Descartes University, Paris, France. [email protected].
  • 2. Groupe Hospital St. Joseph, Paris, France.
  • 3. Anticancer Center, Centre Antoine-Lacassagne, Nice, France.
  • 4. Jean Minjoz Hospital, Besançon, France.
  • 5. Bichat Hospital, Paris, France.
  • 6. Beaujon Hospital, Clichy, France.
  • 7. Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France.
  • 8. Physiology Department, Georges Pompidou European Hospital, Paris, France. Inserm UMRS 845, Centre de Recherche, Université Paris-Descartes, Paris, France.
  • 9. Paris Descartes University, Paris, France. Physiology Department, Georges Pompidou European Hospital, Paris, France.
  • 10. Inserm UMRS 845, Centre de Recherche, Université Paris-Descartes, Paris, France.
  • 11. Hybrigenics, Paris, France.
  • 12. ARTIC, Georges Pompidou European Hospital, Paris, France.
  • 13. Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France. Paris Descartes University, Paris, France.
PMID: 25013124 DOI: 10.1158/1078-0432.CCR-13-3247
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.

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