Background: Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and\nthe combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage.\nThus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone\ndeacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal\nGrowth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to\ndown regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition\n(EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic\ndisorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may\nbe to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the\npossible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR.\nMethod/Design: V-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell\ncarcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration\nof cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from\nday âË?â??14 with a titration strategy in each patient (target serum level of 50ââ?¬â??100 Ã?¼g/ml). Primary end point is the\nobjective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size,\ncalculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit\nfor rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18\nresponses. Secondary endpoints are time to progression, duration of response, overall survival, safety.\nObjectives of the translational study are the evaluation on tumor samples of markers of treatment efficacy/resistance (i.e. Ã?³H2AX, p21/WAF, RAD51, XRCC1, EGFR, p-EGFR, Ki-67) and specific markers of VPA HDAC inhibitory\nactivity (histones and proteins acetylation, Histone deacetylase isoforms) as well as valproate test, histones and\nproteins acetylation of peripheral blood mononuclear cell, tested on blood samples at baseline and at different\ntime points during treatment.\nDiscussion: Overall, this study could provide a less toxic and more effective first-line chemotherapy regimen in\npatients with recurrent/metastatic squamous cell carcinoma of the head and neck by demonstrating the feasibility and\nefficacy of cisplatin/cetuximab plus valproic acid. Moreover, correlative studies could help to identify responder\npatients, and will add insights in the mechanism of the synergistic interaction between these agents.
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