SAVER: sodium valproate for the epigenetic reprogramming of high-risk oral epithelial dysplasia—a phase II randomised control trial study protocol

Abstract

Background Sodium valproate (VPA) has been associated with a reduced risk of head and neck cancer development. The potential protective mechanism of action is believed to be via inhibition of histone deacetylase and subsequent epigenetic reprogramming. SAVER is a phase IIb open-label, randomised control trial of VPA as a chemopreventive agent in patients with high-risk oral epithelial dysplasia (OED). The aim of the trial is to gather preliminary evidence of the clinical and biological effects of VPA upon OED and assess the feasibility and acceptability of such a trial, with a view to inform a future definitive phase III study. Methods One hundred and ten patients with high-risk OED will be recruited from up to 10 secondary care sites in the UK and randomised into either VPA or observation only for 4 months. Women of childbearing potential will be excluded due to the teratogenic properties of VPA. Tissue and blood samples will be collected prior to randomisation and on the last day of the intervention/observation-only period (end of 4 months). Clinical measurement and additional safety bloods will be taken at multiple time points during the trial. The primary outcome will be a composite, surrogate endpoint of change in lesion size, change in grade of dysplasia and change in LOH profile at 8 key microsatellite regions. Feasibility outcomes will include recruitment targets, compliance with the study protocol and adverse effects. A qualitative sub-study will explore patient experience and perception of the trial. Discussion The current management options for patients with high-risk OED are limited and mostly include surgical resection and clinical surveillance. However, there remains little evidence whether surgery can effectively lead to a notable reduction in the risk of oral cancer development. Similarly, surveillance is associated with concerns regarding delayed diagnosis of OED progressing to malignancy. The SAVER trial provides an opportunity to investigate the effects of a repurposed, inexpensive and well-tolerated medication as a potential chemopreventive strategy for patients with high-risk OED. The clinical and biological findings of SAVER will inform the appropriateness, design and feasibility of a definitive phase III trial. Trial registration The trial is registered with the European Clinical Trials Database (Eudra-CT 2018-000197-30). (http://www.isrctn.com/ISRCTN12448611). The trial was prospectively registered on 24/04/2018.

Early-Phase Interventional Trials in Oral Cancer Prevention

“…Chemoprevention studies should ideally recruit participants at increased risk of progression to cancer to maximize (i) the event rate (oral cancer development) and (ii) the potential benefit to the patient. Therefore, chemoprevention trials should selectively recruit patients with a prognostic marker associated with a higher risk of oral cancer development, such as OED and/or the presence of LOH at key loci [30,31]. Unfortunately, the vast majority of previous chemoprevention trials have instead recruited individuals at variable risk of progression; for example, patients with a diagnosis of oral leukoplakia with/without OED.…”

“…Molecular endpoints should be chosen based on good pre-clinical data that have accurately defined the mechanism of action of the drug under investigation; the endpoint should represent an on-target effect of the drug that is also associated with future risk of cancer development [31,32,34,[40][41][42][43][44]64,70].…”

“…A composite endpoint consists of two or more distinct endpoints, known as components [71]. Both the Mallery trial [34] and the SAVER trial [31] use the same composite surrogate endpoint, which combines clinical, histological and molecular endpoints associated with cancer progression in OED. The benefit of combining endpoints in this way is increased power to detect differences in the primary endpoint due to an increased number of 'events'; this, in theory, allows smaller trials at lower cost and is attractive in the case of OED where the event rate (oral cancer development) is low.…”

“…This method is used in the SAVER trial, where, in patients presenting with a new leukoplakia suspicious for dysplasia, a screening biopsy for the trial also serves as the diagnostic biopsy. Patients scheduled for surgery will have a punch biopsy at the time of surgery (at the 4-month point) and those who are to be kept under observation undergo a second biopsy for the purposes of the trial [31]. This window design is suitable for drugs with well-characterized pharmacokinetic profiles but where bioactivity in target tissue is yet to be established; for example, in drug repurposing trials [74].…”

“…Both time-and dose-dependent reductions in the incidence of HNC were demonstrated (HR 0.57 95%CI 0.39-0.85); in addition, there is a plausible mechanism of action for cancer prevention via HDAC inhibition, and therefore this is an attractive option for chemoprevention trials in oral cancer. The SAVER trial is a multi-centre, randomised controlled trial of SV in oral epithelial dysplasia in the UK and aims to recruit 110 participants to SV 500 mg BD or observation arm [31]. This is a window of opportunity trial; patients randomised to the treatment arm will take SV for 4 months, at which point the surrogate end points will be captured and patients will revert to their pre-determined management pathway (surgery or close surveillance).…”