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

A B S T R A C T PurposeEpigenetic 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 MethodsMajor eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score Յ 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. ResultsBelinostat 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 ϭ .036). ConclusionEpigenetic therapy with belinostat demonstrates tumor stabilization and is generally welltolerated. HR23B expression was associated with disease stabilization.

Epigenetic regulation of hepatic tumor-initiating cells

“…The progression-free and overall survival was 2.6 and 6.6 months, respectively. Epigenetic therapy with belinostat displayed well-tolerated and disease stabilization, and more studies are needed to further determine the efficacy and benefits with belinostat treatment in HCC patients (119). Obviously, questions remain regarding whether epigenetic therapy alone or in combination with conventional chemotherapy will be more effective in eradicating T-IC than currently available adjuvant therapeutics for the improvement of therapeutic outcome.…”

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

“…In preclinical investigation, belinostat inhibited cell growth in a HCC cell line, whereas vorinostat sensitized HCC cells to acetylation of p53 and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis [69]. Moreover, in a multi-center phase I/II clinical trial, belinostat was found to stabilize inoperable advanced HCC [105]. Furthermore, Lin et al [106] reported that HDAC inhibitors induced cell death may be accompanied with simultaneously activating tumor-progression genes.…”

“…On the other hand, brivanib, which targets VEGFR, PDGFR and FGFR, also failed to prolong OS (Table 1) in a phase III trial conducted to investigate its efficacy as a first line therapy even though it had a more favorable toxicity profile than sorafenib [89,90]. Moreover, another phase III, randomized, placebo-controlled study investigated the efficacy of brivanib after sorafenib failure and the authors reported that, in comparison to placebo, brivanib resulted in a longer median TTP but insignificant increase in the OS (Table 1) [91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108].…”

Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress

“…Belinostat is a novel pandeacetylase inhibitor that has been clinically tested in patients with solid tumors, such as liver cancer (9), ovarian cancer (10), malignant pleural mesothelioma (11) and thymic epithelial tumors (12), as well as in patients with hematological malignancies (13,14). Favorable antineoplastic effects of belinostat in combination with bortezomib have been reported (15)(16)(17)(18), however, there has been no study evaluating the effect of the combination on renal cancer cells and investigating ER stress induction as a mechanism of action.…”