Phase i study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours

Roberto Pili, B. Salumbides, M. Zhao, S. Altiok, D. Qian, J. Zwiebel, M. A. Carducci, M. A. Rudek

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Background: Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumour sensitivity to retinoids. The objective of this study was to determine the safety, tolerability, and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor entinostat in combination with 13-cis retinoic acid (CRA) in patients with solid tumours. Methods: Patients with advanced solid tumours were treated with entinostat orally once weekly and with CRA orally twice daily × 3 weeks every 4 weeks. The starting dose for entinostat was 4 mg m -2 with a fixed dose of CRA at 1 mg kg 1 per day. Entinostat dose was escalated by 1 mg m -2 increments. Pharmacokinetic concentrations of entinostat and CRA were determined by LC/MS/MS. Western blot analysis of peripheral blood mononuclear cells and tumour samples were performed to evaluate target inhibition. Results: A total of 19 patients were enroled. The maximum tolerated dose (MTD) was exceeded at the entinostat 5 mg m -2 dose level (G3 hyponatremia, neutropenia, and anaemia). Fatigue (G1 or G2) was a common side effect. Entinostat exhibited substantial variability in clearance (147%) and exposure. CRA trough concentrations were consistent with prior reports. No objective responses were observed, however, prolonged stable disease occurred in patients with prostate, pancreatic, and kidney cancer. Data further showed increased tumour histone acetylation and decreased phosphorylated ERK protein expression. Conclusion: The combination of entinostat with CRA was reasonably well tolerated. The recommended phase II doses are entinostat 4 mg m -2 once weekly and CRA 1 mg kg -1 per day. Although no tumour responses were seen, further evaluation of this combination is warranted.

Original languageEnglish (US)
Pages (from-to)77-84
Number of pages8
JournalBritish Journal of Cancer
Volume106
Issue number1
DOIs
StatePublished - Jan 3 2012
Externally publishedYes

Fingerprint

NSC 153174
Isotretinoin
Histone Deacetylase Inhibitors
Tretinoin
Neoplasms
Pharmacokinetics
entinostat
Maximum Tolerated Dose
Hyponatremia
Kidney Neoplasms
Retinoids
Acetylation
Neutropenia
Pancreatic Neoplasms
Histones
Fatigue
Anemia
Blood Cells
Prostatic Neoplasms
Western Blotting

Keywords

  • histone deacetylase inhibitor
  • retinoic acid receptor
  • solid tumours

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase i study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours. / Pili, Roberto; Salumbides, B.; Zhao, M.; Altiok, S.; Qian, D.; Zwiebel, J.; Carducci, M. A.; Rudek, M. A.

In: British Journal of Cancer, Vol. 106, No. 1, 03.01.2012, p. 77-84.

Research output: Contribution to journalArticle

Pili, Roberto ; Salumbides, B. ; Zhao, M. ; Altiok, S. ; Qian, D. ; Zwiebel, J. ; Carducci, M. A. ; Rudek, M. A. / Phase i study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours. In: British Journal of Cancer. 2012 ; Vol. 106, No. 1. pp. 77-84.
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AU - Salumbides, B.

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AU - Altiok, S.

AU - Qian, D.

AU - Zwiebel, J.

AU - Carducci, M. A.

AU - Rudek, M. A.

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AB - Background: Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumour sensitivity to retinoids. The objective of this study was to determine the safety, tolerability, and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor entinostat in combination with 13-cis retinoic acid (CRA) in patients with solid tumours. Methods: Patients with advanced solid tumours were treated with entinostat orally once weekly and with CRA orally twice daily × 3 weeks every 4 weeks. The starting dose for entinostat was 4 mg m -2 with a fixed dose of CRA at 1 mg kg 1 per day. Entinostat dose was escalated by 1 mg m -2 increments. Pharmacokinetic concentrations of entinostat and CRA were determined by LC/MS/MS. Western blot analysis of peripheral blood mononuclear cells and tumour samples were performed to evaluate target inhibition. Results: A total of 19 patients were enroled. The maximum tolerated dose (MTD) was exceeded at the entinostat 5 mg m -2 dose level (G3 hyponatremia, neutropenia, and anaemia). Fatigue (G1 or G2) was a common side effect. Entinostat exhibited substantial variability in clearance (147%) and exposure. CRA trough concentrations were consistent with prior reports. No objective responses were observed, however, prolonged stable disease occurred in patients with prostate, pancreatic, and kidney cancer. Data further showed increased tumour histone acetylation and decreased phosphorylated ERK protein expression. Conclusion: The combination of entinostat with CRA was reasonably well tolerated. The recommended phase II doses are entinostat 4 mg m -2 once weekly and CRA 1 mg kg -1 per day. Although no tumour responses were seen, further evaluation of this combination is warranted.

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