SAVER

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.

SAVER is a phase II clinical trial with embedded mechanistic and feasibility studies. It is randomized, double blind and placebo controlled with a planned recruitment of 110 patients. The randomisation is in the ratio 2 SV (73 patients) :1 placebo (37 patients). The study population includes patients with premalignant oral lesions that have a histological diagnosis of oral epithelial dysplasia (OED) and are at high risk (considered to be at least 20% over 5 years of malignant transformation).

The aim of this phase II trial is to investigate the effects of sodium valproate as epigenetic chemopreventive therapy on high risk oral dysplasia. In particular, we will establish: clinical activity, mechanism of action and, feasibility of conducting such research in the NHS, in order to inform a decision on a larger phase III trial.

The primary endpoint is a measure of clinical activity and a surrogate – it is a composite of clinical, pathology and molecular lesional changes which has been previously used, with peer review, in randomised trials, within the same field (20). It is derived from clinical measurement, photographs and punch biopsy tissue comparing baseline to primary endpoint (4 months). Approximately 10 research sites are to be opened to recruitment in the UK and Ireland. 

Inclusion Criteria:

1. Recent (< 12 months) histological diagnosis of confirmation of OED according to the World Health Organisation (WHO) criteria (i.e: Patients may be eligible who have a longstanding diagnosis of OED diagnosis but then would need either a recent biopsy (< 12months) or to enter the screening route to randomization)

2. Index lesion* which must be:

a. Accessible

b. Measurable

c. Amenable to clinical photography

d. Oral cavity, lip or oropharynx

e. Minimum lesion size: 10mm x 10mm, or > = 100mm2

(* other ‘non-index’ lesions in the same patient may be present and do not make the patient ineligible)

3. Treatment plan for either surgical resection, or for surveillance of the lesion by means of clinical and photographic follow-up.

4. The index lesion must be considered to be deemed at high risk (i.e. estimated > 20% over 5 years) of malignant transformation, i.e.:

a. WHO severe OED or carcinoma in situ, or

b. WHO mild or moderate OED, with at least one additional high risk feature(s) from the list below:

i. non-smoker

ii. lesion size > 200mm2

iii. lateral tongue site

iv. mucosal speckling or heterogeneous appearance

v. excised OSCC during previous 5 years (but not within previous 6 months).

5. The patient is fully informed, has received PIS (Patient Information Sheet) & considered during a ‘cooling-off’ period, is competent to consent, age > = 18, and is able to comply with minimum attendance requirements. 

Exclusion Criteria:

1. Synchronous or metachronous OSCC (i.e. at time of screening or within 6 months)

2. Active malignancy outside head and neck region (with exception of non-melanoma skin cancer)

3. Inflammatory co-existing oral lesions: lichen planus, fungal (candidiasis) oral lesions, scleroderma

4. OSCC susceptible conditions e.g. Fanconi Anaemia, Blooms syndrome, Ataxia Telangectasia, Li Fraumeni syndrome etc.

5. Clinical and/or histopathological diagnosis of oral submucous fibrosis

6. Immunosupression, however, low dose i.e. < 10mg/day prednisolone, or equivalent steroids, are not considered an exclusion.

7. Chronic previous or current use of Sodium Valproate

8. Diagnosed epilepsy that has chronic previous or current use of any antiepileptic therapy

9. Obesity (Body Mass Index >= 30)

10. Known relative or absolute contraindications to Sodium Valproate (as listed in British National Formulary), and specifically:

a. Acute porphyria

b. Known or suspected mitochondrial disorders

c. Personal or family history of severe hepatic dysfunction, current hepatic dysfunction (as evidenced by LFTs outwith reference  range and prolonged prothrombin time)

d. Past history or current pancreatitis

e. Women with child-bearing potential (< 2 years post menopause), pregnancy, breast feeding. (This is iterated in more detail in SOP as per appendix 1)

f. Potential drug interactions (particularly antipsychotic and anticonvulsant medications, MAO inhibitors, antidepressants, benzodiazepines), specifically patients taking phenobarbital, primodone, carbopenem antibiotics (imipenem, panipenem, meropenem), cimetidine, erythromycin, lamotrigine, olanzapine, pivmecillinam, sodium oxybate, zidovudine, carbamazepine, phenytoin, rifampicin. 

Research Nurse: Iram Asif (iram.asif@elht.nhs.uk)

Administrator: Oncology Research Team