TY - JOUR
T1 - Phase i study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours
AU - Pili, R.
AU - Salumbides, B.
AU - Zhao, M.
AU - Altiok, S.
AU - Qian, D.
AU - Zwiebel, J.
AU - Carducci, M. A.
AU - Rudek, M. A.
N1 - Funding Information:
We thank NCI-CTEP for supporting the study and Schering AG for purchasing Accutane. We also thank Dr Sharyn Baker for his scientific input, Ping He for her technical support, and Susan Davidson for her quality assurance of the data. This work was supported in part by The Maryland Cigarette Restitution Research Fund, The Flight Attendant Medical Research Institute, The Translational Research Initiative CTEP-NCI (RP), The Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins (P30 CA006973), and U01 CA 70095 (MAC).
PY - 2012/1/3
Y1 - 2012/1/3
N2 - 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.
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.
KW - histone deacetylase inhibitor
KW - retinoic acid receptor
KW - solid tumours
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U2 - 10.1038/bjc.2011.527
DO - 10.1038/bjc.2011.527
M3 - Article
C2 - 22134508
AN - SCOPUS:84855340600
SN - 0007-0920
VL - 106
SP - 77
EP - 84
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 1
ER -