A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer

Fang Fang, Curt Balch, Jeanne Schilder, Timothy Breen, Shu Zhang, Changyu Shen, Lang Li, Carol Kulesavage, Anthony J. Snyder, Kenneth Nephew, Daniela Matei

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Aberrant DNA methylation is a hallmark of cancer, and DNA methyltransferase inhibitors have demonstrated clinical efficacy in hematologic malignancies. On the basis of preclinical studies indicating that hypomethylating agents can reverse platinum resistance in ovarian cancer cells, the authors conducted a phase 1 trial of lowdose decitabine combined with carboplatin in patients with recurrent, platinum-resistant ovarian cancer. METHODS: Decitabine was administered intravenously daily for 5 days, before carboplatin (area under the curve, 5) on Day 8 of a 28-day cycle. By using a standard 3 + 3 dose escalation, decitabine was tested at 2 dose levels: 10 mg/m2 (7 patients) or 20 mg/m2 (3 patients). Peripheral blood mononuclear cells (PBMCs) and plasma collected on Days 1 (pretreatment), 5, 8, and 15 were used to assess global (LINE-1 repetitive element) and gene-specific DNA methylation. RESULTS: Dose-limiting toxicity (DLT) at the 20-mg/m2 dose was grade 4 neutropenia (2 patients), and no DLTs were observed at 10 mg/m2. The most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1-2. One complete response was observed, and 3 additional patients had stable disease for ≥6 months. LINE-1 hypomethylation on Days 8 and 15 was detected in DNA from PBMCs. Of 5 ovarian cancer-associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on Days 8 and 15. CONCLUSIONS: Repetitive low-dose decitabine is tolerated when combined with carboplatin in ovarian cancer patients, and demonstrates biological (ie, DNA-hypomethylating) activity, justifying further testing for clinical efficacy.

Original languageEnglish
Pages (from-to)4043-4053
Number of pages11
JournalCancer
Volume116
Issue number17
DOIs
StatePublished - Sep 1 2010

Fingerprint

decitabine
Carboplatin
Platinum
Ovarian Neoplasms
DNA Methylation
Neutropenia
DNA
Blood Cells
Long Interspersed Nucleotide Elements
BRCA1 Gene
Methyltransferases
Anorexia
Hematologic Neoplasms
Nausea
Abdominal Pain
Area Under Curve
Vomiting
Fatigue
Ovarian epithelial cancer
Hypersensitivity

Keywords

  • Chemosensitization
  • Decitabine
  • Epigenetic biomarkers
  • Ovarian cancer
  • Platinum resistance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer. / Fang, Fang; Balch, Curt; Schilder, Jeanne; Breen, Timothy; Zhang, Shu; Shen, Changyu; Li, Lang; Kulesavage, Carol; Snyder, Anthony J.; Nephew, Kenneth; Matei, Daniela.

In: Cancer, Vol. 116, No. 17, 01.09.2010, p. 4043-4053.

Research output: Contribution to journalArticle

Fang, Fang ; Balch, Curt ; Schilder, Jeanne ; Breen, Timothy ; Zhang, Shu ; Shen, Changyu ; Li, Lang ; Kulesavage, Carol ; Snyder, Anthony J. ; Nephew, Kenneth ; Matei, Daniela. / A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer. In: Cancer. 2010 ; Vol. 116, No. 17. pp. 4043-4053.
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AU - Balch, Curt

AU - Schilder, Jeanne

AU - Breen, Timothy

AU - Zhang, Shu

AU - Shen, Changyu

AU - Li, Lang

AU - Kulesavage, Carol

AU - Snyder, Anthony J.

AU - Nephew, Kenneth

AU - Matei, Daniela

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N2 - BACKGROUND: Aberrant DNA methylation is a hallmark of cancer, and DNA methyltransferase inhibitors have demonstrated clinical efficacy in hematologic malignancies. On the basis of preclinical studies indicating that hypomethylating agents can reverse platinum resistance in ovarian cancer cells, the authors conducted a phase 1 trial of lowdose decitabine combined with carboplatin in patients with recurrent, platinum-resistant ovarian cancer. METHODS: Decitabine was administered intravenously daily for 5 days, before carboplatin (area under the curve, 5) on Day 8 of a 28-day cycle. By using a standard 3 + 3 dose escalation, decitabine was tested at 2 dose levels: 10 mg/m2 (7 patients) or 20 mg/m2 (3 patients). Peripheral blood mononuclear cells (PBMCs) and plasma collected on Days 1 (pretreatment), 5, 8, and 15 were used to assess global (LINE-1 repetitive element) and gene-specific DNA methylation. RESULTS: Dose-limiting toxicity (DLT) at the 20-mg/m2 dose was grade 4 neutropenia (2 patients), and no DLTs were observed at 10 mg/m2. The most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1-2. One complete response was observed, and 3 additional patients had stable disease for ≥6 months. LINE-1 hypomethylation on Days 8 and 15 was detected in DNA from PBMCs. Of 5 ovarian cancer-associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on Days 8 and 15. CONCLUSIONS: Repetitive low-dose decitabine is tolerated when combined with carboplatin in ovarian cancer patients, and demonstrates biological (ie, DNA-hypomethylating) activity, justifying further testing for clinical efficacy.

AB - BACKGROUND: Aberrant DNA methylation is a hallmark of cancer, and DNA methyltransferase inhibitors have demonstrated clinical efficacy in hematologic malignancies. On the basis of preclinical studies indicating that hypomethylating agents can reverse platinum resistance in ovarian cancer cells, the authors conducted a phase 1 trial of lowdose decitabine combined with carboplatin in patients with recurrent, platinum-resistant ovarian cancer. METHODS: Decitabine was administered intravenously daily for 5 days, before carboplatin (area under the curve, 5) on Day 8 of a 28-day cycle. By using a standard 3 + 3 dose escalation, decitabine was tested at 2 dose levels: 10 mg/m2 (7 patients) or 20 mg/m2 (3 patients). Peripheral blood mononuclear cells (PBMCs) and plasma collected on Days 1 (pretreatment), 5, 8, and 15 were used to assess global (LINE-1 repetitive element) and gene-specific DNA methylation. RESULTS: Dose-limiting toxicity (DLT) at the 20-mg/m2 dose was grade 4 neutropenia (2 patients), and no DLTs were observed at 10 mg/m2. The most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1-2. One complete response was observed, and 3 additional patients had stable disease for ≥6 months. LINE-1 hypomethylation on Days 8 and 15 was detected in DNA from PBMCs. Of 5 ovarian cancer-associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on Days 8 and 15. CONCLUSIONS: Repetitive low-dose decitabine is tolerated when combined with carboplatin in ovarian cancer patients, and demonstrates biological (ie, DNA-hypomethylating) activity, justifying further testing for clinical efficacy.

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KW - Epigenetic biomarkers

KW - Ovarian cancer

KW - Platinum resistance

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