A phase I/II study of belinostat (PXD101) in patients with unresectable hepatocellular carcinoma

Abstract

15081 Background: Hepatocellular carcinoma (HCC) is a common cause of cancer morbidity and mortality. It is a highly aggressive tumor with 90% presenting with unresectable disease, resulting in a median survival of 3–6 months. Inhibitors of histone deacetylase (HDAC) have been demonstrated in HCC cell lines and xenografts to induce apoptosis and tumor regression, and have anti-proliferative, anti-metastatic and anti-invasive effects. Belinostat (N-hydroxy-3-[phenylsulphamoylphenyl] acryl amide) is a novel, low molecular weight, HDAC inhibitor. The Cancer Therapeutic Research Group (CTRG) is conducting a phase I/II study of belinostat as the first line therapy for pts with unresectable HCC. The phase I study aims to determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Methods: Patient eligibilities include histologically or cytologically confirmed unresectable HCC, ECOG = 2, adequate hematologic, renal and hepatic functions. The dose of belinostat was started at 600 mg/m2/day i.v. on day 1–5 every 3 weeks; with increment of 300 mg/m2/day up to 1200 mg/m2/day. Dose limiting toxicities (DLT) are defined as grade 4 hematological toxicity or grade 3 or 4 nonhematological toxicity during cycle 1 (according to NCI CTC v3), or treatment delay >2 weeks. The MTD is defined as the dose below which ≥ 2 of 3 or ≥ 2 of 6 patients experiencing DLT. After determination of the MTD, 3 additional patients will be treated at this dose to further define toxicity. Results: From June-December 2006, 12 pts were entered; 3 were treated at level I (600 mg/m2/day), 3 at level 2 (900 mg/m2/day), and 6 at level 3 (1200 mg/m2/day). There were no DLTs on level 1, 2 or 3. Therefore, the MTD of belinostat was not reached. Overall toxicities were WBC gr. 0/1/2/3/4: 12/0/0/0/0, ANC gr. 0/1/2/3/4: 12/0/0/0/0; Hb gr. 0/1/2/3/4: 4/7/0/1/0; platelet gr. 0/1/2/3/4: 8/4/0/0/0; lethargy gr. 0/1/2/3: 12/0/0/0/0, phlebitis gr. 0/1/2/3: 10/0/2/0; Cough gr. 0/1/2/3: 9/0/3/0; Nausea gr. 0/1/2/3: 7/3/2/0 and vomiting gr. 0/1/2/3: 9/3/0/0. Conclusions: At the maximum dose of 1200 mg/m2/day (level 3), MTD has not been reached. Belinostat is very well tolerated. Phase II study will be started at dose level 1200 mg/m2/day. Sponsor: The Division of Cancer Treatment and Diagnosis, National Cancer Institute, USA. No significant financial relationships to disclose.