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

Sponsor

Barretos Cancer Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT02608736

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Squamous Cell Carcinoma	Drug: Valproic Acid Drug: Placebo	Early Phase 1

Detailed Description

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).

Study Design

Study Type:

Interventional

Actual Enrollment :

42 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Prevention

Official Title:

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

Study Start Date :

Dec 1, 2015

Actual Primary Completion Date :

Dec 1, 2016

Actual Study Completion Date :

Jul 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Valproic Acid Valproic acid will be orally administered in a total dose of 1500mg per day (500mg, every 8 hours), for three months.	Drug: Valproic Acid Half of the participants will receive valproic acid orally for three months. Saliva and blood will be sampled in the study entry. The participants will be followed with blood tests every month for three cycles. After the third cycle, saliva and blood will be sampled once more. Finally, histone acetylation and DNMT expression will be studied comparing the samples collected in different timelines and comparing them to saliva collected in placebo arm. Other Names: Divalproex Depakene Depacon Depakote
Placebo Comparator: Placebo Placebo will be orally administered in a total dose of three capsules per day (every 8 hours), for three months.	Drug: Placebo The other half of the participants will receive placebo for three months. Saliva and blood will be sampled in the study entry. The participants will be followed with blood tests every month for three cycles. After the third cycle, saliva and blood will be sampled once more. Finally, histone acetylation and DNMT expression will be studied comparing the samples collected in different timelines and comparing them to saliva collected in valproic acid arm. Other Names: Inert, not active

Arm

Intervention/Treatment

Experimental: Valproic Acid

Valproic acid will be orally administered in a total dose of 1500mg per day (500mg, every 8 hours), for three months.

Drug: Valproic Acid

Half of the participants will receive valproic acid orally for three months. Saliva and blood will be sampled in the study entry. The participants will be followed with blood tests every month for three cycles. After the third cycle, saliva and blood will be sampled once more. Finally, histone acetylation and DNMT expression will be studied comparing the samples collected in different timelines and comparing them to saliva collected in placebo arm.

Other Names:

Divalproex

Depakene

Depacon

Depakote

Placebo Comparator: Placebo

Placebo will be orally administered in a total dose of three capsules per day (every 8 hours), for three months.

Drug: Placebo

The other half of the participants will receive placebo for three months. Saliva and blood will be sampled in the study entry. The participants will be followed with blood tests every month for three cycles. After the third cycle, saliva and blood will be sampled once more. Finally, histone acetylation and DNMT expression will be studied comparing the samples collected in different timelines and comparing them to saliva collected in valproic acid arm.

Other Names:

Inert, not active

Outcome Measures

Primary Outcome Measures

Changes in protein or histone acetylation [Three months after study enrollment]
Saliva samples will be collected in baseline and three months after study enrolment. Histone acetylation will be quantified (through ELISA method) and compared in the same arm (if there will be a change in histone acetylation when looking at these different timelines) and between arms (if one group will have or will not have more histone acetylation than the other).

Secondary Outcome Measures

Incidence of Treatment-Emergent Adverse Events [Day 1 of each new cycle up to 3 months (3 months of treatment and 3 months of follow-up), in other words, from day 1 of the first cycle until the date of first documented emergent adverse event, assessed up to 6 months]
Evaluation of incidence of treatment-induced adverse events at the beginning of each new cycle (day 1, every 30 days, for a total of six months) using Common Toxicity Criteria for Adverse Effects (CTCAE v.4.0).
Change in DNA methyltransferases expression. (DNMT) [Three months after study enrollment]
Saliva samples will be collected in baseline and three months after study enrolment. DNA methyltransferases expression (through microarray method) will be compared in the same arm (if there will be a change in DNMT expression when looking at these different timelines) and between arms (if one group will have or will not have a different DNMT expression when compared to the other).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.