Chemoprevention of Head and Neck Squamous Cell Carcinoma (HNSCC) With Valproic Acid

Phase 0 Clinical Trial With Valproic Acid as a Chemopreventive Agent in Patients With Head and Neck Squamous Cell Carcinoma Previously Treated

This study evaluates the addition of valproic acid as a chemopreventive drug in head and neck squamous cell carcinoma (HNSCC) patients that do not have signs of recurrence or residual disease. The participants will be randomized 1:1 (valproic acid : placebo). The primary outcome is to document histone acetylation and DNA methyltransferase expression (DNMT) in saliva collected from participants when comparing valproic acid arm with placebo arm.

Chemoprevention is an attractive strategy to reduce the incidence of squamous cell carcinoma of the head and neck, although past trials have not demonstrated its feasibility.

Valproic acid (VA) is a modifier of epigenetic events as it is an histone deacetylase inhibitor and causes DNMT degradation. The histone deacetylase inhibitors (e.g. VA) encompasses a new class of anti-tumor drugs, that can affect multiple pathways related to tumor initiation and progression due to histone and non-histone protein acetylation and DNMT degradation. VA promote histone acetylation when orally administered with a dose of 20-40 mg/kg, per day or 1000/1500 mg, per day.

Initially the authors will study saliva from participants documenting if there is saliva histone acetylation and if a difference in DNMT expression in saliva exists when comparing valproic acid arm to placebo arm (biological validation) after giving placebo or valproic acid for three months.

This will be the initial step of a bigger project. If authors prove that there will be a difference in histone acetylation and/or DNMT expression between groups they will launch a randomized, double blind, placebo control clinical trial (phase 3 clinical trial), to evaluate VA action as a chemopreventive agent in HNSCC patients who usually carries a high chance to develop recurrence (stages III/IV) or second primary malignancies (stages I/II/III/IV).

Inclusion Criteria:

• Patients that signed the formal consent;
• Previous history of head and neck squamous cell carcinoma with no more than three years of follow-up;
• History of squamous cell carcinoma in the following sub-sites: oral cavity, oropharynx, larynx and hypopharynx;
• Absence of active malignant disease (HNSCC) with at least three months of follow-up (without signs of residual disease, recurrence or second primary invasive tumors);
• Normal liver, hematologic and renal function.
• Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1 or 2;
• Smoking history (current smokers or former smokers). Former users were defined as patients who had quit smoking at least one year prior to diagnosis and smoked more than 100 cigarettes in their lifetime.

Exclusion Criteria:

• Any active malignancy;
• History of invasive malignancies (other than HNSCC) diagnosed within the last 2 years (controlled non-melanoma skin cancer are an exception);
• History of hepatitis B, hepatitis C, HIV, chronic liver disease or chronic pancreatic disease;
• Any comorbid medical or psychiatric disorder that it is not well controlled;
• Patients under immunosuppression or under systemic corticosteroid therapy to treat any active autoimmune disease;
• Patients that still have documented toxicities greater than grade 1 (CTCEA NCI v4.0) due to the previously treated HNSCC;
• Patients that are pregnant or breast-feeding;
• Patients that are in routine use of the following medications due to drug interaction: phenytoin, carbamazepine, barbiturates, chlorpromazine, diazepam, clonazepam, lamotrigine, primidone, amitriptyline, nortriptyline, ethosuximide, warfarin, tolbutamide or topiramate;
• Any medical condition or mental disorder that can potentially increase their risk during the trial (e.g. epilepsy, active infection, schizophrenia);
• Patients that are already under valproic acid use due to neurological or psychiatric disorders;
• Patients that are allergic/intolerant to valproic acid;
• Patients with alcoholism history within the past year or that was under alcoholism treatment in the same period;
• Institutionalized patients.