Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial

Abstract

BackgroundRecurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to down regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition (EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic disorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may be to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the possible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR.Method/DesignV-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell carcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration of cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from day −14 with a titration strategy in each patient (target serum level of 50–100 μg/ml). Primary end point is the objective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size, calculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit for rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18 responses. Secondary endpoints are time to progression, duration of response, overall survival, safety.Objectives of the translational study are the evaluation on tumor samples of markers of treatment efficacy/resistance (i.e. γH2AX, p21/WAF, RAD51, XRCC1, EGFR, p-EGFR, Ki-67) and specific markers of VPA HDAC inhibitory activity (histones and proteins acetylation, Histone deacetylase isoforms) as well as valproate test, histones and proteins acetylation of peripheral blood mononuclear cell, tested on blood samples at baseline and at different time points during treatment.DiscussionOverall, this study could provide a less toxic and more effective first-line chemotherapy regimen in patients with recurrent/metastatic squamous cell carcinoma of the head and neck by demonstrating the feasibility and efficacy of cisplatin/cetuximab plus valproic acid. Moreover, correlative studies could help to identify responder patients, and will add insights in the mechanism of the synergistic interaction between these agents.EudraCT Number2014-001523-69Trial registrationClinicalTrials.gov number, NCT02624128

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

“…Although butyrate was used in the previous studies as total HDAC inhibitor (15), pharmacokinetic studies have confirmed its lower cardiac distribution, compared to VPA (41, 42). In addition, phase II/III clinical trials have confirmed that VPA is a safe medicine for the therapy some cancers (43, 44). More importantly, VPA is also an established drug for the long-term therapy of epilepsy because of its HDAC inhibition activity (45).…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…Clearly, large prospective randomised studies are necessary to determine whether VPA has anticancer properties of clinical significance. One study of great interest is the V‐CHANCE study which is a Phase II clinical trial evaluating the concomitant standard administration of cisplatin and cetuximab in combination with oral VPA given daily from day‐14 (with a titration strategy to achieve target concentrations) in patients with recurrent/metastatic squamous cell carcinoma of the head and neck who have never been treated with first‐line chemotherapy …”

The EMT spectrum and therapeutic opportunities

“…However, various components of the NuRD complex, and specifically the HDACs, will confer drug resistance to cancer cells (Fu et al ., ; Li et al ., ; Sakamoto et al ., ). Consequently, HDAC inhibitors such as vorinostat, mocetinostat, and valproic acid are currently being evaluated as anti‐EMT agents (Bruzzese et al ., ; Caponigro et al ., ; Lan et al ., ; Meidhof et al ., ; Sakamoto et al ., ; Schech et al ., ; Schobert and Biersack, ).…”