A Phase 1 Clinical Trial of Guadecitabine and Carboplatin In Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic And Pharmacodynamic Analyses

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 1 study of guadecitabine and carboplatin (G+C) in patients with recurrent, platinum resistant high-grade serous ovarian cancer (OC), primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC). Experimental Design: Guadecitabine was administered once daily on Days 1-5 followed by carboplatin IV 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). 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 de-escalation of guadecitabine to 30 mg/m² and of carboplatin to AUC4. No DLTS were observed in the subsequent 14 patients. Grade ≥3AEs ≥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 six 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 re-expression in paired tumor biopsies/ascites were recorded. Conclusions: G+C was tolerated and induced clinical responses in a heavily pretreated platinum resistant OC population, supporting a subsequent randomized phase 2 trial.

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