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.
OBJECTIVE
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.


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/m(2) per day (level 1), 900 mg/m(2) per day (level 2), 1,200 mg/m(2) 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/m(2) 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).


CONCLUSIONS
Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.
Department of Clinical Oncology, State Key Lab of Oncology in South China, Prince of Wales Hospital Shatin, Chinese University of Hong Kong, Hong Kong, China. winnieyeo@cuhk.edu.hk
Winnie
W
Yeo
Hyun C
HC
Chung
Stephen L
SL
Chan
Ling Z
LZ
Wang
Robert
R
Lim
Joel
J
Picus
Michael
M
Boyer
Frankie K F
FK
Mo
Jane
J
Koh
Sun Y
SY
Rha
Edwin P
EP
Hui
Hei C
HC
Jeung
Jae K
JK
Roh
Simon C H
SC
Yu
Ka F
KF
To
Qian
Q
Tao
Brigette B
BB
Ma
Anthony W H
AW
Chan
Joanna H M
JH
Tong
Charles
C
Erlichman
Anthony T C
AT
Chan
Boon C
BC
Goh
D000328:Adult; D000368:Aged; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D015897:Comorbidity; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018572:Disease-Free Survival; D057890:Epigenomics; D005260:Female; D019694:Hepatitis B, Chronic / Q000453:epidemiology; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000453:epidemiology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016019:Survival Analysis
D054316:Biomarkers, Pharmacological; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C513287:RAD23B protein, human; D013449:Sulfonamides; D045643:DNA Repair Enzymes; C487081:belinostat