Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma

A multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the mayo phase II consortium and the cancer therapeutics research group

Winnie Yeo, Hyuncheol Chung, Stephen L. Chan, Ling Z. Wang, Robert Lim, Joel Picus, Michael Boyer, Frankie K.F. Mo, Jane Koh, SunYoung Rha, Edwin P. Hui, Hei C. Jeung, Jae K. Roh, Simon C.H. Yu, Ka F. To, Qian Tao, Brigette B. Ma, Anthony W.H. Chan, Joanna H.M. Tong, Charles Erlichman & 2 others Anthony T.C. Chan, Boon C. Goh

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Purpose: Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II. Patients and Methods: Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m2 per day (level 1), 900 mg/m2 per day (level 2), 1,200 mg/m2 per day (level 3), and 1,400 mg/m 2 per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response. Results: Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m2 without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036). Conclusion: Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.

Original languageEnglish
Pages (from-to)3361-3367
Number of pages7
JournalJournal of Clinical Oncology
Volume30
Issue number27
DOIs
Publication statusPublished - 2012 Sep 20

Fingerprint

Therapeutic Human Experimentation
Epigenomics
Hepatocellular Carcinoma
Pharmacokinetics
Biomarkers
Maximum Tolerated Dose
Disease-Free Survival
Neoplasms
Histone Deacetylase Inhibitors
Survival
Therapeutics
Liver Diseases
Chronic Disease
belinostat

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yeo, Winnie ; Chung, Hyuncheol ; Chan, Stephen L. ; Wang, Ling Z. ; Lim, Robert ; Picus, Joel ; Boyer, Michael ; Mo, Frankie K.F. ; Koh, Jane ; Rha, SunYoung ; Hui, Edwin P. ; Jeung, Hei C. ; Roh, Jae K. ; Yu, Simon C.H. ; To, Ka F. ; Tao, Qian ; Ma, Brigette B. ; Chan, Anthony W.H. ; Tong, Joanna H.M. ; Erlichman, Charles ; Chan, Anthony T.C. ; Goh, Boon C. / Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma : A multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the mayo phase II consortium and the cancer therapeutics research group. In: Journal of Clinical Oncology. 2012 ; Vol. 30, No. 27. pp. 3361-3367.
@article{1537ca99c3f8489ba0f3d4758dbc024a,
title = "Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: A multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the mayo phase II consortium and the cancer therapeutics research group",
abstract = "Purpose: Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II. Patients and Methods: Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m2 per day (level 1), 900 mg/m2 per day (level 2), 1,200 mg/m2 per day (level 3), and 1,400 mg/m 2 per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response. Results: Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m2 without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4{\%} and 45.2{\%}, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58{\%} and 14{\%}, respectively (P = .036). Conclusion: Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.",
author = "Winnie Yeo and Hyuncheol Chung and Chan, {Stephen L.} and Wang, {Ling Z.} and Robert Lim and Joel Picus and Michael Boyer and Mo, {Frankie K.F.} and Jane Koh and SunYoung Rha and Hui, {Edwin P.} and Jeung, {Hei C.} and Roh, {Jae K.} and Yu, {Simon C.H.} and To, {Ka F.} and Qian Tao and Ma, {Brigette B.} and Chan, {Anthony W.H.} and Tong, {Joanna H.M.} and Charles Erlichman and Chan, {Anthony T.C.} and Goh, {Boon C.}",
year = "2012",
month = "9",
day = "20",
doi = "10.1200/JCO.2011.41.2395",
language = "English",
volume = "30",
pages = "3361--3367",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "27",

}

Yeo, W, Chung, H, Chan, SL, Wang, LZ, Lim, R, Picus, J, Boyer, M, Mo, FKF, Koh, J, Rha, S, Hui, EP, Jeung, HC, Roh, JK, Yu, SCH, To, KF, Tao, Q, Ma, BB, Chan, AWH, Tong, JHM, Erlichman, C, Chan, ATC & Goh, BC 2012, 'Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: A multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the mayo phase II consortium and the cancer therapeutics research group', Journal of Clinical Oncology, vol. 30, no. 27, pp. 3361-3367. https://doi.org/10.1200/JCO.2011.41.2395

Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma : A multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the mayo phase II consortium and the cancer therapeutics research group. / Yeo, Winnie; Chung, Hyuncheol; Chan, Stephen L.; Wang, Ling Z.; Lim, Robert; Picus, Joel; Boyer, Michael; Mo, Frankie K.F.; Koh, Jane; Rha, SunYoung; Hui, Edwin P.; Jeung, Hei C.; Roh, Jae K.; Yu, Simon C.H.; To, Ka F.; Tao, Qian; Ma, Brigette B.; Chan, Anthony W.H.; Tong, Joanna H.M.; Erlichman, Charles; Chan, Anthony T.C.; Goh, Boon C.

In: Journal of Clinical Oncology, Vol. 30, No. 27, 20.09.2012, p. 3361-3367.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma

T2 - A multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the mayo phase II consortium and the cancer therapeutics research group

AU - Yeo, Winnie

AU - Chung, Hyuncheol

AU - Chan, Stephen L.

AU - Wang, Ling Z.

AU - Lim, Robert

AU - Picus, Joel

AU - Boyer, Michael

AU - Mo, Frankie K.F.

AU - Koh, Jane

AU - Rha, SunYoung

AU - Hui, Edwin P.

AU - Jeung, Hei C.

AU - Roh, Jae K.

AU - Yu, Simon C.H.

AU - To, Ka F.

AU - Tao, Qian

AU - Ma, Brigette B.

AU - Chan, Anthony W.H.

AU - Tong, Joanna H.M.

AU - Erlichman, Charles

AU - Chan, Anthony T.C.

AU - Goh, Boon C.

PY - 2012/9/20

Y1 - 2012/9/20

N2 - Purpose: Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II. Patients and Methods: Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m2 per day (level 1), 900 mg/m2 per day (level 2), 1,200 mg/m2 per day (level 3), and 1,400 mg/m 2 per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response. Results: Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m2 without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036). Conclusion: Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.

AB - Purpose: Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II. Patients and Methods: Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m2 per day (level 1), 900 mg/m2 per day (level 2), 1,200 mg/m2 per day (level 3), and 1,400 mg/m 2 per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response. Results: Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m2 without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036). Conclusion: Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.

UR - http://www.scopus.com/inward/record.url?scp=84866758581&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866758581&partnerID=8YFLogxK

U2 - 10.1200/JCO.2011.41.2395

DO - 10.1200/JCO.2011.41.2395

M3 - Article

VL - 30

SP - 3361

EP - 3367

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 27

ER -