title: Phase I/II study of azacitidine, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy.
abstract: BACKGROUND
  Methylation-mediated silencing of genes contributes to docetaxel resistance in prostate cancer. We propose that azacitidine, a demethylating agent, can reverse docetaxel resistance.
  
  
  METHODS
  Metastatic castration-resistant prostate cancer (mCRPC) patients, who progressed during or within 6 months of docetaxel chemotherapy, were eligible. Fifteen and 7 patients were treated in phase I and II, respectively. In phase I, azacitidine and docetaxel were alternately escalated in a standard 3 + 3 design. All patients received prednisone 5 mg twice daily continuously. Patients were evaluated for toxicity and efficacy. Growth arrest and DNA damage-inducible alpha (GADD45A) methylation was measured before and after azacitidine treatment in the first cycle in phase I patients.
  
  
  RESULTS
  In phase I, no dose-limiting toxicity was observed. At the highest dose (azacitidine 150 mg/m(2) daily for 5 days followed by docetaxel 75 mg/m(2) on day 6), Grade 4 neutropenia was frequent, but infrequent with growth factor. Six patients in the phase II study received the highest dose including growth factor support. The sixth phase II patient died because of neutropenic sepsis. After data and safety monitoring board review, the phase II dose was reduced to azacitidine 75 mg/m(2) daily for 5 days followed by docetaxel 75 mg/m(2) on day 6 with growth factor support. Prostate-specific antigen response was seen in 10 of 19 evaluable patients and objective response was observed in 3 of 10 evaluable patients. Significant demethylation of GADD45A was observed with azacitidine treatment.
  
  
  CONCLUSIONS
  The combination of azacitidine, docetaxel, and prednisone with growth factor support is active in mCRPC patients.
authors.affiliation: University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL. Electronic address: rsingal@med.miami.edu.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Singal
authors.affiliation: University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Ramachandran
authors.affiliation: University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL.
authors.forename: Edna
authors.initials: E
authors.lastname: Gordian
authors.affiliation: University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL.
authors.forename: Carlos
authors.initials: C
authors.lastname: Quintero
authors.affiliation: University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL.
authors.forename: Isildinha M
authors.initials: IM
authors.lastname: Reis
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics*; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics*; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D016896:Treatment Outcome; D000097642:GADD45 Proteins
chemical_list: D000970:Antineoplastic Agents; D001374:Azacitidine; D018797:Cell Cycle Proteins; D000077143:Docetaxel; D009687:Nuclear Proteins; D011241:Prednisone; D043823:Taxoids; C439070:GADD45A protein, human; D000097642:GADD45 Proteins
keywords: Chemotherapy; GADD45A; Methylation; Taxotere; Vidaza