A Phase I Clinical Trial of Guadecitabine and Carboplatin in Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic, and Pharmacodynamic Analyses

Clin Cancer Res. 2018 May 15;24(10):2285-2293. doi: 10.1158/1078-0432.CCR-17-3055. Epub 2018 Mar 2.


Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here, we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase I study of guadecitabine and carboplatin in patients with recurrent, platinum-resistant high-grade serous ovarian cancer, primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC).Experimental Design: Guadecitabine was administered once daily on days 1 to 5 followed by carboplatin i.v. on day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4.Results: Twenty patients were enrolled and treated. Median age was 56 years (38-72 years). The median number of prior regimens was 7 (1-14). In the first cohort (N = 6), the starting doses were guadecitabine 45 mg/m2 and carboplatin AUC5. Four patients experienced dose-limiting toxicity (DLT; neutropenia and thrombocytopenia), leading to dose deescalation of guadecitabine to 30 mg/m2 and of carboplatin to AUC4. No DLTs were observed in the subsequent 14 patients. Grade ≥3 adverse events ≥10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small-intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR), and 6 patients had stable disease (SD) >3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene reexpression in paired tumor biopsies/ascites were recorded.Conclusions: Guadecitabine and carboplatin were tolerated and induced clinical responses in a heavily pretreated platinum-resistant ovarian cancer population, supporting a subsequent randomized phase II trial. Clin Cancer Res; 24(10); 2285-93. ©2018 AACR.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Azacitidine / administration & dosage
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacokinetics
  • Carboplatin / administration & dosage
  • Carboplatin / pharmacokinetics
  • Drug Monitoring
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Middle Aged
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology*
  • Platinum Compounds / pharmacology
  • Platinum Compounds / therapeutic use
  • Recurrence
  • Retreatment


  • Platinum Compounds
  • guadecitabine
  • Carboplatin
  • Azacitidine