Title: SAVER - Sodium Valproate for Epigenetic Reprogramming in the Management of High Risk Oral Epithelial Dysplasia
Funder: Department of Health and Social Care

Abstract: Proof of Concept: A recent large epidemiological study showed that long-term use of the antiepileptic agent sodium valproate (SV) reduces the incidence of head and neck cancer in high-risk patients. SV is known to inhibit histone deacetylase (HDAC) activity, which may explain the putative chemopreventative effect. HDAC inhibitors are licenced for the treatment of cutaneous T-cell lymphoma, and importantly another epigenetic modulator, azacytidine is used to prevent malignant transformation of high-risk myelodysplastic syndromes. Animal models also support a role for HDACi in cancer prevention activity. Finally, epigenetic changes have a proven central role in oral epithelial dysplasia (OED) and its progression to carcinoma. Hypothesis: SV will reduce the rate of malignant transformation in patients with high risk OED through epigenetic modifications. Aims: 1) To establish clinical activity of SV as chemopreventive therapy in high-risk OED. 2) To explore the hypothesis that SV reduces progression through epigenetic reprogramming. 3) To investigate the feasibility and acceptability of a phase III randomised controlled trial of SV chemoprevention. Design: Randomised (2 SV: 1 Placebo), double-blind, placebo controlled phase II clinical trial. Population: Patients with OED at high risk of progression to carcinoma (malignant transformation) who have a standard of care therapeutic plan for either close surveillance or surgical resection (patients on either pathway may be recruited). Interventions: Treatment arm: Sodium Valproate 1000mg/day Control arm: Placebo Outcomes & Assessments: 1) Clinical, histological and molecular activity measured using a previously established surrogate composite endpoint which combines changes in: a. Clinical appearance (dimension) b. Histological grade of dysplasia c. Allelic imbalance (3p14, 9p21, 17p13) This primary endpoint is measured before and after a 4-month of SV or placebo treatment. 2) Mechanistic endpoints will explore the hypothesised epigenetic mechanism of action: histone acetylation in circulating white cells, and corresponding tissue specific changes in pre- and post- treatment biopsies of the oral lesions. Additionally, expression of gene targets in a tissue- & disease-specific panel will be assessed by mRNA transcriptional profiling (Nanostring). DNA promoter methylation most strongly linked with OED malignant progression (P16, DCC, EDNRB) will also be studied, while downstream effects on proliferation, apoptosis and senescence will be assessed by IHC. 3) Feasibility: rates of recruitment, screening:randomisation, drop-out, completion of treatment, toxicity. An embedded qualitative study with a purposively selected sample of patients including topic-guided, face-to-face semi-structured interviews will focus on patients’ accounts. Sample Size and Analysis: Randomised phase II design based on exact binomial probabilities, allowing for unequal allocation ratios: 110 patients randomised 2:1 SV: Placebo, assuming 10% dropout. The primary endpoint is response rate using a composite end-point (clinical/pathology/molecular). Analyses shall be carried out assuming a binary response rate with further ordinal modelling carried out should the data allow. Feasibility shall be assessed based on the ability of the study to meet recruitment targets. Economic benefit: reduction in malignant transformation of OED will outweigh the modest costs of SV.

Lay abstract: Individuals can develop patches (oral dysplasia) on the lining of the mouth which are at risk of developing into cancer. Standard treatments include surgery or close surveillance, although these treatments are not completely effective, as up to 25% of patients progress to oral cancer even after surgery. Oral cancer treatments can be curative, especially when caught early, but the side effects include damage to speech, swallowing, appearance and reduction in quality of life, which are permanent. Additionally treatment for oral cancer carries a high economic burden and the World Health Organisation has recommended a shift in policy towards early diagnosis and prevention. Survival rates for oral cancer have remained largely unchanged for decades, at around 50-55% overall survival by 5 years. There is, therefore, a need to develop and evaluate new prevention treatments for this condition. It is thought that more effective treatment for oral dysplasia would reduce the incidence of oral cancer. A recent large study has reported that long-term use of sodium valproate, a drug normally used to treat epilepsy, can reduce the risk of developing head and neck cancers by about one third. This relatively safe drug is known to have effects on what is known as ‘epigenetics’. Epigenetics literally means "upon genetics" and describes a series of biological processes that affect how our genes behave. Changing the epigenetics of a cancer cell can lead it to gene changes that stop it growing. If sodium valproate alters the epigenetic make-up of precancer cells, it might prevent them from developing into mouth cancer. Similar drugs have been proven effective in preventing leukaemia (blood cancer) in patients diagnosed with blood cancer precursors. This information has been discussed with patients who have past experience of head and neck cancer and oral dysplasia, and they have helped to guide the design of SAVER. Patients have emphasized the psychological distress caused by the diagnosis of dysplasia and dealing with a disease that increases the risk of cancer and has no definitive therapy. In particular, they have supported the principle of approaching suitable patients for inclusion within high quality clinical studies, as the current evidence base is so poor. The aim of this small (phase II) trial is to investigate the effects of sodium valproate on high risk oral cancer precursors in a controlled setting. Patients will take either sodium valproate or a placebo (a similar looking tablet that is inactive) alongside their normal treatment. They would be randomly allocated to one of the treatments and neither the patient nor doctor would know which tablet they were taking. A series of measurements will be taken to investigate whether (i) oral cancer precursors will reduce in size, (ii) cellular abnormality will reverse, and (iii) DNA changes will disappear. The patients would undergo a very small (5mm) biopsy prior to, and after treatment, and also some blood tests. The patients would be carefully monitored throughout and after the study. The study results would help to decide on the need for a larger phase III trial which would be mandatory before introducing sodium valproate as standard therapy to this group of patients. Hence, this smaller phase II trial is being used to justify the need for a larger and more definitive phase III trial that would look at cancer development as the main outcome.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL