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Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors.

ABSTRACT: Thymic epithelial tumors are rare malignancies, and there is no standard treatment for patients with advanced disease in whom chemotherapy has failed. Antitumor activity of histone deacetylase (HDAC) inhibitors in this disease has been documented, including one patient with thymoma treated with the pan-HDAC inhibitor belinostat.Patients with advanced thymic epithelial malignancies in whom at least one line of platinum-containing chemotherapy had failed were eligible for this study. Other eligibility criteria included adequate organ function and good performance status. Belinostat was administered intravenously at 1 g/m(2) on days 1 to 5 of a 21-day cycle until disease progression or development of intolerance. The primary objective was response rate in patients with thymoma.Of the 41 patients enrolled, 25 had thymoma, and 16 had thymic carcinoma; patients had a median of two previous systemic regimens (range, one to 10 regimens). Treatment was well tolerated, with nausea, vomiting, and fatigue being the most frequent adverse effects. Two patients achieved partial response (both had thymoma; response rate, 8%; 95% CI, 2.2% to 25%), 25 had stable disease, and 13 had progressive disease; there were no responses among patients with thymic carcinoma. Median times to progression and survival were 5.8 and 19.1 months, respectively. Survival of patients with thymoma was significantly longer than that of patients with thymic carcinoma (median not reached v 12.4 months; P = .001). Protein acetylation, regulatory T-cell numbers, and circulating angiogenic factors did not predict outcome.Belinostat has modest antitumor activity in this group of heavily pretreated thymic malignancies. However, the duration of response and disease stabilization is intriguing, and additional testing of belinostat in this disease is warranted.

SUBMITTER: Giaccone G

PROVIDER: S-EPMC3107761 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors.

Giaccone Giuseppe G Rajan Arun A Berman Arlene A Kelly Ronan J RJ Szabo Eva E Lopez-Chavez Ariel A Trepel Jane J Lee Min-Jung MJ Cao Liang L Espinoza-Delgado Igor I Spittler John J Loehrer Patrick J PJ

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20110418 15

<h4>Purpose</h4>Thymic epithelial tumors are rare malignancies, and there is no standard treatment for patients with advanced disease in whom chemotherapy has failed. Antitumor activity of histone deacetylase (HDAC) inhibitors in this disease has been documented, including one patient with thymoma treated with the pan-HDAC inhibitor belinostat.<h4>Patients and methods</h4>Patients with advanced thymic epithelial malignancies in whom at least one line of platinum-containing chemotherapy had faile ...[more]

PMID: 21502553

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Project description:BackgroundNo standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy.MethodsBetween Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250.Findings49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1-46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3-36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5-29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0-26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3-4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions during treatment (five were new-onset disorders), the most common of which was pure red-cell aplasia. Two (4%) patients died; one was attributed to disease progression and the other to disease-related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab.InterpretationCixutumumab monotherapy is well-tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation.FundingDivision of Cancer Treatment and Diagnosis at the National Cancer Institute (National Institutes of Health), ImClone Systems.

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Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors.

Publications

Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors.

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