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| |  Belinostat Shows Promising Activity in Combination with Carboplatin and Paclitaxel in Ovarian Cancer Patients: Presented at AACR-NCI-EORTC By Crina Frincu-Mallos, PhD SAN FRANCISCO, CA -- October 26, 2007 -- The results of a phase 1b dose-escalation portion of a phase 2 trial indicate that the combination of belinostat with carboplatin and paclitaxel was well tolerated in patients with relapsed ovarian carcinoma, researchers reported here at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. There was a strong rationale for combining histone deacetylase (HDAC) inhibitors with platinum-based agents and taxanes. Belinostat is known to enhance acetylation in the presence of taxanes, inducing apoptosis through altered microtubule dynamics. It also causes DNA relaxation through increased histone acetylation, making the cancer cells more susceptible to platinum-induced DNA damage, the researchers explained in a presentation here on October 25. Neil J. Finkler, MD, FACOG, FACS, Director, Gynecologic Oncology Program, Florida Hospital Cancer Institute, Orlando, Florida, presented the results on behalf of an international team of researchers from Denmark, United Kingdom, and the United States. This is a phase 2, open label, non-randomised, multicentre study with a Simon 2-stage design, which enrolled 23 women in the phase 1b portion of the trial. The 23 women accrued had a median age of 59.5 years (range, 39-79 years), diagnosed with ovarian cancer for a median of 3.1 years (range, 1.2-8.7 years), who had at least one prior regimen (range, 1-4 regimens). The study's combination treatment was administered intravenously in a 21-day cycle, as follows: belinostat 1000 mg/m2/day over 30 to 60 minutes on days 1 to 5, while on day 3 patients received infusions of paclitaxel (175 mg/m2, over 3-hours, at least 2-hours post-belinostat) and carboplatin (AUC of 5, over 30 to 60 minutes, immediately after paclitaxel) administered together. The combination was generally well tolerated, said Dr. Finkler. The most common adverse events were nausea (n=19), fatigue (n=17), and vomiting (n=13). However, there were a few grade 4 adverse events in these patients: increased aspartate aminotransferase (n=4) and increased alanine transaminase (n=4). A total of five patients were terminated from the study due to serious adverse effects, according to researchers. Dr. Finkler indicated that 15 patients exhibited reduction in the size of their tumours, the combination being active in both platinum-sensitive and platinum-resistant patients. At this time, preliminary results show that there are two complete responses, two confirmed partial responses, and four unconfirmed partial responses in the ongoing 13 patients, say the researchers. "We are very encouraged by the level of activity we have seen [with belinostat in combination with carboplatin and paclitaxel] for the treatment of relapsed ovarian cancer, including activity against platinum-resistant tumours," said Dr. Finkler. The substantial antitumour activity supports further testing of this combination in this patient population, in the phase 2 expansion of the trial, the researchers said. The accrual goal for the phase 2 portion of the study is 32 patients. Funding for this study was provided by CuraGen Corporation, Branford, Connecticut, United States, and TopoTarget A/S, Copenhagen, Denmark.
[Presentation title: Phase II Multicenter Trial of Belinostat (PXD101) in Combination With Carboplatin and Paclitaxel (BelCap) for Patients With Relapsed Ovarian Cancer. Abstract C223]
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