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

Abstract

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.

• Authors: Daniela Matei, Sharad Ghamande, Lynda Roman, Angeles Alvarez Secord, John Nemunaitis, Merry Jennifer Markham, Kenneth P Nephew, Simone Jueliger, Aram Oganesian, Sue Naim, Xiang Yao Su, Harold Keer, Mohammad Azab, Gini F Fleming
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 10 Pg. 2285-2293 (05 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29500276 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Platinum Compounds
• guadecitabine
• Carboplatin
• Azacitidine

Topics

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