Oral epithelial dysplasia Oral Health Diseases of oral cavity, salivary glands and jaws
Conditions
Interventions
Current intervention as of 07/07/2022:
SAVER is a randomised (1 control [no medication]: 2 Sodium Valproate), unblinded, multi-centre placebo-controlled phase II clinical trial investigating the use o
including ‘step-up’ phase x 2 weeks, at 500mg once daily.
On 26/04/2021 a substantial amendment request was submitted with a trial re-design from double-blinded randomised trial with IMP/Placebo to u
Sponsors
University of Liverpool
Eligibility
Sex/Gender
All
Age
55 Years to 100 Years
Inclusion criteria
Inclusion criteria: Current participant inclusion criteria as of 10/07/2024: 1. Recent (=100 mm2 (* 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.: 4.1. WHO severe OED or 4.2. WHO mild or moderate OED, with at least one additional high-risk feature(s) from the list below: 4.2.1. Non-smoker (less than 100 cigarettes or equivalent over whole lifetime) 4.2.2. Lesion size >200 mm2 4.2.3. Lateral tongue site 4.2.4. Mucosal speckling or heterogeneous appearance 4.2.5. 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, and is able to comply with minimum attendance requirements 6. Aged =55 years Previous participant inclusion criteria as of 07/07/2022 to 10/07/2024: 1. Recent (=100 mm2 (* 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.: 4.1. WHO severe OED or 4.2. WHO mild or moderate OED, with at least one additional high-risk feature(s) from the list below: 4.2.1. Non-smoker (less than 100 cigarettes or equivalent over whole lifetime) 4.2.2. Lesion size >200 mm2 4.2.3. Lateral tongue site 4.2.4. Mucosal speckling or heterogeneous appearance 4.2.5. 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, and is able to comply with minimum attendance requirements 6. Aged =18 years Previous participant 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 (<12 months) or to enter the screening route to randomization) 2. Index lesion* which mu
Exclusion criteria
Exclusion criteria: Current participant exclusion criteria as of 10/07/2024: 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. OSCC susceptible conditions e.g. Fanconi Anaemia, Blooms syndrome, Ataxia Telangectasia, Li Fraumeni syndrome etc. 4. Clinical and/or histopathological diagnosis of oral submucous fibrosis 5. Immunosuppression, however, low dose i.e. = 35) 9. Known relative or absolute contraindications to Sodium Valproate (as listed in British National Formulary), and specifically: 9.1. Acute porphyria 9.2. Known or suspected mitochondrial disorders 9.3. Personal or family history of severe hepatic dysfunction, as defined by Child-Pugh Group C (see appendix 5) 9.4. current hepatic dysfunction (as evidenced by LFTs significantly outwith reference range or prolonged prothrombin time) 9.5. Past history or current pancreatitis 9.6. Women with child-bearing potential. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Women who have undergone total hysterectomy or bilateral salpingo-oophorectomy or who are in a postmenopausal state are eligible for the SAVER trial. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range will be used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy (HRT). Females on HRT must discontinue HRT to allow confirmation of postmenopausal status before study enrolment. Otherwise, they must be considered non-eligible to participate in this trial and excluded. 9.7. 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, high dose salicylates including aspirin >75mg daily (patients taking low dose aspirin 75mg daily are eligible) 9.8. Patients with suicidal ideation and behaviour should be excluded from the trial. Patients should also be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. 9.9. Patients with known or suspected mitochondrial disease, systemic lupus erythematosus or hyperammonaemia Previous participant 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, Bloom's syndrome, Ataxia Telangectasia, Li Fraumeni syndrome etc 5. Clinical and/or histopathological diagnosis of oral submucous fibrosis 6. Immunosuppression, however, low dose i.e. < 10m
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Clinical activity will be measured using the commonly used surrogate end point that has evolved over several MD Anderson studies in the same field. The primary endpoint itself will be measured using the definitions of Mallery and it will be derived as a composite score of changes in lesion size, changes in histological grade, and LOH definition at 4 months from the date of commencement of study drug. Assessment of lesion size Lesion size will be calculated based on a first assessment of clinical images with lesional size mm2 = pixels of lesional area x 100/(pixels of 1 centimeter unit on the calibration device in the same image)2. Secondary assessment of lesion size will be calculated based on the estimated elliptical area given by the longest length of the lesion and the associated perpendicular width. Lesion size response will be then measured calculated on a 7 point scale ranging from -3 to 3 based on the change in lesion size between pre and post treatment assessment. Specifically, the relationship between score and outcome is as follows: • 75% or more decrease = 3 • 50% to 74% decrease = 2 • 25% to 49% decrease = 1 • 0% to 24% decrease or increase = 0 • 25% to 49% increase = -1 • 50% to 74% increase = -2 • 75% or more increase = -3 Assessment of histology response score Formally, a 0 to 8 grade scale will be used to obtain the histological score as follows: • 0 = normal with or without hyperkeratosis • 1 = atypia with crisply defined clinical margins • 2 = mild dysplasia • 3 = mild-moderate dysplasia • 4 = moderate dysplasia • 5 = moderate-severe dysplasia • 6 = severe dysplasia • 7 = carcinoma in situ • 8 = invasive SCC Assessment of LOH response score A series of microsatellite markers will be selected for LOH analyses. These are 8 corresponding loci and associated genes: • 3p14 [D3S1007 (VHL), D3S1234 (FHIT)] • 9p21 [D9S171, D9S1748 (P16/CDKN2A), D9S1751 (P16)] • 9p22 (IFN- a) • 17p13 [D17S786 (P53) and TP53] For each loci, a score of +1 is given if it i | — |
Secondary
| Measure | Time frame |
|---|---|
| Measured at 4 months from the date of commencement of study drug: 1. Disease control rate, defined as treatment response or stable disease against patients with disease progression using the composite responsiveness score defined in Section 9.3.1 of SAVER’s protocol 2. Clinical response, as measured by assessment of lesion size as in Section 9.3.1 Section 9.3.1 of SAVER’s protocol 3. Histological response, as measured by assessment of histology response score as in Section 9.3.1 Section 9.3.1 of SAVER’s protocol 4. LOH Response score, as measured in 9.3.1 Section 9.3.1 of SAVER’s protocol 5. WHO grade of OED (or SCC) in entire whole resection specimen (where any oral resection is performed within trial period) 6. Toxicity, measured using CTCAE (Version 4) classifications | — |
Countries
England, Scotland, United Kingdom
Contacts
Public ContactTrial Manager
Outcome results
None listed