title: Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.
abstract: BACKGROUND
  Sequential treatment with azacitidine can induce re-expression of epigenetically silenced genes through genomic DNA hypomethylation and reverse carboplatin resistance of epithelial ovarian cancer cells. A phase 1b-2a clinical trial of this sequential combination of azacitidine and carboplatin was initiated in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer.
  
  
  METHODS
  Patients with pathologically confirmed intermediate-grade or high-grade epithelial ovarian cancer who developed disease progression within 6 months (resistant disease, n = 18 patients) or during a platinum-based therapy (refractory disease, n = 12 patients) were eligible. All patients had measurable disease.
  
  
  RESULTS
  Thirty patients received a total of 163 cycles of treatment. This regimen produced 1 complete response, 3 partial responses (overall response rate [ORR], 13.8%), and 10 cases of stable disease among 29 evaluable patients. For those patients who achieved clinical benefits, the median duration of the treatment was 7.5 months. The median progression-free survival (PFS) and overall survival (OS) for all patients were 3.7 months and 14 months, respectively. Patients with platinum-resistant disease achieved an ORR of 22%, with a median PFS of 5.6 months and a median OS of 23 months. The predominant toxicities were fatigue and myelosuppression. Correlative studies indicated that DR4 methylation in peripheral blood leukocytes was decreased during treatment in 3 of 4 objective responders (75%), but in only 5 of 13 nonresponders (38%).
  
  
  CONCLUSIONS
  To the authors' knowledge, the results of the current study provide the first clinical evidence that a hypomethylating agent may partially reverse platinum resistance in patients with ovarian cancer. Further clinical evaluation of hypomethylating agents in combination with carboplatin is warranted.
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. siqingfu@mdanderson.org
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Revathy
authors.initials: R
authors.lastname: Iyer
authors.forename: John J
authors.initials: JJ
authors.lastname: Kavanagh
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: Charles F
authors.initials: CF
authors.lastname: Levenback
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Judith K
authors.initials: JK
authors.lastname: Wolf
authors.forename: David M
authors.initials: DM
authors.lastname: Gershenson
authors.forename: Maurie
authors.initials: M
authors.lastname: Markman
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage* / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage*; D000077216:Carcinoma, Ovarian Epithelial; D019175:DNA Methylation; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy
chemical_list: D000964:Antimetabolites, Antineoplastic; D016190:Carboplatin; D001374:Azacitidine