Phase I/II study of azacitidine, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy

Rakesh Singal, Kavitha Ramachandran, Edna Gordian, Carlos Quintero, Wei Zhao, Isildinha Reis

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Introduction Methylation-mediated silencing of genes contributes to docetaxel resistance in prostate cancer. We propose that azacitidine, a demethylating agent, can reverse docetaxel resistance. Patients and 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/m2 daily for 5 days followed by docetaxel 75 mg/m2 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/m2 daily for 5 days followed by docetaxel 75 mg/m2 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. Conclusion The combination of azacitidine, docetaxel, and prednisone with growth factor support is active in mCRPC patients.

Original languageEnglish
Pages (from-to)22-31
Number of pages10
JournalClinical Genitourinary Cancer
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2015

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docetaxel
Azacitidine
Castration
Prednisone
Prostatic Neoplasms
Intercellular Signaling Peptides and Proteins
Therapeutics
Methylation
Clinical Trials Data Monitoring Committees

Keywords

  • Chemotherapy
  • GADD45A
  • Methylation
  • Taxotere
  • Vidaza

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Phase I/II study of azacitidine, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. / Singal, Rakesh; Ramachandran, Kavitha; Gordian, Edna; Quintero, Carlos; Zhao, Wei; Reis, Isildinha.

In: Clinical Genitourinary Cancer, Vol. 13, No. 1, 01.01.2015, p. 22-31.

Research output: Contribution to journalArticle

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abstract = "Introduction Methylation-mediated silencing of genes contributes to docetaxel resistance in prostate cancer. We propose that azacitidine, a demethylating agent, can reverse docetaxel resistance. Patients and 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/m2 daily for 5 days followed by docetaxel 75 mg/m2 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/m2 daily for 5 days followed by docetaxel 75 mg/m2 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. Conclusion The combination of azacitidine, docetaxel, and prednisone with growth factor support is active in mCRPC patients.",
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