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

Abstract

Purpose: 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 and methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT01100944.

Fig 1.

Time to progression (TTP) in (A) the overall population and (B) patients with thymoma and thymic carcinoma. Overall survival (OS) in (C) the overall population and (D) patients with thymoma and thymic carcinoma. (E) TTP and (F) OS in patients with intrathoracic disease only v patients with extrathoracic disease (with or without intrathoracic sites).

Fig 2.

Global protein and tubulin acetylation in patient peripheral blood mononuclear cells (PBMCs). PBMCs were isolated at day 1 of cycle one preinfusion (C1D1 pre), day 3 of cycle one 1 hour postinfusion (C1D3 post), and day 1 of cycle two preinfusion (C2D1 pre). PBMCs were viably frozen, thawed, and stained for (A) acetylated lysine and (B) acetylated tubulin and analyzed by flow cytometry. Fluorescence intensity was normalized to C1D1 preinfusion. Line graphs show fold change at C1D3 and C2D1 for (A) global protein acetylation and (B) tubulin acetylation.

Fig A1.

Example of pleural-based tumors that responded to belinostat treatment in one patient with partial response.