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.

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/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). CONCLUSION: Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.

Alteration of hTERT full-length variant expression level showed different gene expression profiles and genomic copy number changes in breast cancer.

We analyzed hTERT splicing patterns with respect to telomerase activity in breast cancer. Using a cDNA microarray in 22 cell lines, we observed the difference in expression profiling based on the different levels of full-length variant expression with 71 selected genes. Using 33 known genes that act with the telomerase complex, we performed unsupervised clustering with all cell lines, and found a clustering tendency related to the full-length variant expression level. Using array-based CGH, highly altered genomic copy number changes were found more often in MCF-7 (159 genes) than in MDA-MB-231 (109 genes) and MDA-MB-435 (49 genes), suggesting more genomic changes in MCF-7 cells. On comparing MCF-7 with MDA-MB231 and MDA-MB-435 cell lines, we identified 8 genes with different copy numbers, including dystroglycan, which is located in the p12-21.2 area of chromosome 3. In conclusion, alterations in the level of the full-length variant of hTERT showed different gene expression profiles and genomic copy number changes in breast cancer, which require further study into their cause-and-effect relationship.

Infusional fluorouracil, etoposide, and cisplatin (FEP) in advanced and relapsed gastric cancer.

We evaluated the efficacy and tolerability of a combination chemotherapy including infusional fluorouracil (5-FU), etoposide, and cisplatin (FEP) in 89 patients with advanced/relapsed gastric cancer. Primary endpoints were progression-free and overall survival. Secondary endpoints were response rates, response duration, and toxicity. The treatment schedule was as follows: 5-FU 1,000 mg/m2 and etoposide 100 mg/m2 were administered on 3 consecutive days and cisplatin at 80 mg/m2 was administered on day 2, and repeated every 3 weeks. The median times to progression and overall survival were 4 and 8 months, respectively. One-year progression-free and overall survival rates were 10% and 33%, respectively. The overall response rate for 25 eligible patients with measurable disease was 20% (5/25, complete response 2, partial response 3) with median response duration of 7 months. Median actual dose intensities of 5-FU, etoposide, and cisplatin were 700 mg/m2/wk, 70 mg/m2/wk, and 21 mg/m2/wk, respectively. Median relative dose intensities of 5-FU, etoposide, and cisplatin were 0.70, 0.70, and 0.63, respectively. In conclusion, the FEP regimen was found to produce therapeutic results similar to those of other combination chemotherapeutic studies and to have an acceptable toxicity. This regimen could be used as one of the options for advanced gastric cancer chemotherapy in patients unsuitable for doxorubicin-based regimens.