A phase i clinical trial of guadecitabine and carboplatin in platinum-resistant, recurrent ovarian cancer: Clinical, pharmacokinetic, and pharmacodynamic analyses

Daniela Matei, Sharad Ghamande, Lynda Roman, Angeles Alvarez Secord, John Nemunaitis, Merry Jennifer Markham, Kenneth Nephew, Simone Jueliger, Aram Oganesian, Sue Naim, Xiang Yao Su, Harold Keer, Mohammad Azab, Gini F. Fleming

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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 ¼ 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.

Original languageEnglish (US)
Pages (from-to)2285-2293
Number of pages9
JournalClinical Cancer Research
Volume24
Issue number10
DOIs
StatePublished - May 15 2018

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Carboplatin
Platinum
Ovarian Neoplasms
Pharmacokinetics
Clinical Trials
Neutropenia
Ascites
Thrombocytopenia
Fallopian Tube Neoplasms
Hypokalemia
Intestinal Obstruction
Leukopenia
Constipation
SGI-110
Pulmonary Embolism
Epigenomics
Nausea
Vomiting
Anemia
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase i clinical trial of guadecitabine and carboplatin in platinum-resistant, recurrent ovarian cancer : Clinical, pharmacokinetic, and pharmacodynamic analyses. / Matei, Daniela; Ghamande, Sharad; Roman, Lynda; Secord, Angeles Alvarez; Nemunaitis, John; Markham, Merry Jennifer; Nephew, Kenneth; Jueliger, Simone; Oganesian, Aram; Naim, Sue; Su, Xiang Yao; Keer, Harold; Azab, Mohammad; Fleming, Gini F.

In: Clinical Cancer Research, Vol. 24, No. 10, 15.05.2018, p. 2285-2293.

Research output: Contribution to journalArticle

Matei, D, Ghamande, S, Roman, L, Secord, AA, Nemunaitis, J, Markham, MJ, Nephew, K, Jueliger, S, Oganesian, A, Naim, S, Su, XY, Keer, H, Azab, M & Fleming, GF 2018, 'A phase i clinical trial of guadecitabine and carboplatin in platinum-resistant, recurrent ovarian cancer: Clinical, pharmacokinetic, and pharmacodynamic analyses', Clinical Cancer Research, vol. 24, no. 10, pp. 2285-2293. https://doi.org/10.1158/1078-0432.CCR-17-3055
Matei, Daniela ; Ghamande, Sharad ; Roman, Lynda ; Secord, Angeles Alvarez ; Nemunaitis, John ; Markham, Merry Jennifer ; Nephew, Kenneth ; Jueliger, Simone ; Oganesian, Aram ; Naim, Sue ; Su, Xiang Yao ; Keer, Harold ; Azab, Mohammad ; Fleming, Gini F. / A phase i clinical trial of guadecitabine and carboplatin in platinum-resistant, recurrent ovarian cancer : Clinical, pharmacokinetic, and pharmacodynamic analyses. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 10. pp. 2285-2293.
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T2 - Clinical, pharmacokinetic, and pharmacodynamic analyses

AU - Matei, Daniela

AU - Ghamande, Sharad

AU - Roman, Lynda

AU - Secord, Angeles Alvarez

AU - Nemunaitis, John

AU - Markham, Merry Jennifer

AU - Nephew, Kenneth

AU - Jueliger, Simone

AU - Oganesian, Aram

AU - Naim, Sue

AU - Su, Xiang Yao

AU - Keer, Harold

AU - Azab, Mohammad

AU - Fleming, Gini F.

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N2 - 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 ¼ 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.

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