title: Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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 II study is planned.
authors.affiliation: Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France. Paris Descartes University, Paris, France. jacques.medioni@egp.aphp.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Medioni
authors.affiliation: Groupe Hospital St. Joseph, Paris, France.
authors.forename: Gael
authors.initials: G
authors.lastname: Deplanque
authors.affiliation: Anticancer Center, Centre Antoine-Lacassagne, Nice, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.affiliation: Jean Minjoz Hospital, Besançon, France.
authors.forename: Tristan
authors.initials: T
authors.lastname: Maurina
authors.affiliation: Bichat Hospital, Paris, France.
authors.forename: Jean-Michel P
authors.initials: JM
authors.lastname: Rodier
authors.affiliation: Beaujon Hospital, Clichy, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.affiliation: Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France.
authors.forename: Jorge
authors.initials: J
authors.lastname: Allyon
authors.affiliation: Physiology Department, Georges Pompidou European Hospital, Paris, France. Inserm UMRS 845, Centre de Recherche, Université Paris-Descartes, Paris, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Maruani
authors.affiliation: Paris Descartes University, Paris, France. Physiology Department, Georges Pompidou European Hospital, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.affiliation: Inserm UMRS 845, Centre de Recherche, Université Paris-Descartes, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mackenzie
authors.affiliation: Hybrigenics, Paris, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Renaux
authors.affiliation: Hybrigenics, Paris, France.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Dufour-Lamartinie
authors.affiliation: ARTIC, Georges Pompidou European Hospital, Paris, France.
authors.forename: Reza
authors.initials: R
authors.lastname: Elaidi
authors.affiliation: ARTIC, Georges Pompidou European Hospital, Paris, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Lerest
authors.affiliation: Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France. Paris Descartes University, Paris, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Oudard
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000480:Alkynes / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002762:Cholecalciferol / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D000077143:Docetaxel; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000480:Alkynes; D018167:Receptors, Calcitriol; D043823:Taxoids; C579457:VDR protein, human; C409043:inecalcitol; D000077143:Docetaxel; D002762:Cholecalciferol; D017430:Prostate-Specific Antigen