Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer

Abstract

Objectives: Patients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options. Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors.

Methods: A phase II trial of single agent romidepsin, an HDAC inhibitor, was performed in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa. Romidepsin was administered at 13 mg/m(2) as a 4-h intravenous infusion on days 1, 8 and 15 of 28 day cycles, with response assessment by RECIST every 8 weeks.

Results: Objective responses were not observed, although 2 heavily pretreated patients had brief clinical disease stabilization. Observed toxicities were expected, including frequent severe fatigue. Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21(Waf1/Cip1) characteristic of HDAC inhibition, as well as decreased Ki67 staining. Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport. Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors.

Conclusions: Single agent romidepsin has limited activity for the treatment of SCCHN but can effectively achieve tumor-associated HDAC inhibition. Although tolerability of romidepsin in this setting may be limiting, further evaluation of other HDAC inhibitors in combination with active therapies may be justified.

Conflict of interest statement

Conflict of interest statement: None declared.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Fig. 1

A. Stable large lung metastases (arrow) following the initial 2 cycles of romidepsin in a patient (patient #3) with prior chemoradiotherapy and disease progression on four palliative lines of systemic therapy. The pleural effusion seen prior to therapy (dotted arrow) had resolved. B. Results of densitometric analysis indicating modest increase in PMBC histone H3 acetylation following romidepsin administration, and individual responses to therapy. C. Representative western blot of PBMC histone proteins obtained pre-treatment and immediately after the first 4-hour romidepsin infusion, demonstrating histone H3 hyperacetylation (arrow). Positive controls include ex vivo exposure of PBMCs from a non-cancer volunteer (MH) to the HDAC inhibitors trichostatin A (TSA) and romidepsin (Romi). Histone H1 is used as a loading control.

Fig. 2

Formalin-fixed, paraffin embedded pre- and post-treatment tumor biopsy pairs were stained with anti-p21Waf1/Cip1 (A) or Ki67 (B). Tumor cells were scored as 0, 1+ or 2+. The percent positively staining cells is plotted on the y-axis.

Fig. 3

Extent of methylation of individual CpG positions in promoter elements of CDH1 and hMLH1 in baseline and post-romidepsin treated SCCHN tumors as determined by bisulfite PCR followed by pyrosequencing.