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摘要
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 pharmacokinecic ( PK) and pharmacodynamic analyses of the phase I study of guaclecitohine 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/m(2) and carboplatin AUC5 our patients experienced dose-limiting toxicity (DET: neutropenia and thrumbocytopenia), leading to dose deescalation of guadecitabine to 30 mg/m(2) and of carboplatin to AUC4. No DETs were observed in the subsequent 14 patients. Grade >= 3 adverse events >= 10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokolcinia, 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 platinumresistant ovarian cancer population, supporting a subsequent randomized phase II trial.
- 出版日期2018-5-15
- 单位西北大学
