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

Primary Purpose

Head and Neck Squamous Cell Carcinoma

Status
Completed
Phase
Early Phase 1
Locations
Brazil
Study Type
Interventional
Intervention
Valproic Acid
Placebo
Sponsored by
Barretos Cancer Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Head and Neck Squamous Cell Carcinoma focused on measuring head and neck squamous cell carcinoma, histone deacetylases, valproic acid, acetylation, chemoprevention, DNA methyltransferase, methylation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • Barretos Cancer Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Valproic Acid

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Changes in protein or histone acetylation
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
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)
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).

Full Information

First Posted
November 16, 2015
Last Updated
January 30, 2018
Sponsor
Barretos Cancer Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02608736
Brief Title
Chemoprevention of Head and Neck Squamous Cell Carcinoma (HNSCC) With Valproic Acid
Acronym
GAMA
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 Type
Interventional

2. Study Status

Record Verification Date
September 2016
Overall Recruitment Status
Completed
Study Start Date
December 2015 (undefined)
Primary Completion Date
December 2016 (Actual)
Study Completion Date
July 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Barretos Cancer Hospital

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Head and Neck Squamous Cell Carcinoma
Keywords
head and neck squamous cell carcinoma, histone deacetylases, valproic acid, acetylation, chemoprevention, DNA methyltransferase, methylation

7. Study Design

Primary Purpose
Prevention
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
42 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Valproic Acid
Arm Type
Experimental
Arm Description
Valproic acid will be orally administered in a total dose of 1500mg per day (500mg, every 8 hours), for three months.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo will be orally administered in a total dose of three capsules per day (every 8 hours), for three months.
Intervention Type
Drug
Intervention Name(s)
Valproic Acid
Other Intervention Name(s)
Divalproex, Depakene, Depacon, Depakote
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Inert, not active
Intervention Description
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.
Primary Outcome Measure Information:
Title
Changes in protein or histone acetylation
Description
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).
Time Frame
Three months after study enrollment
Secondary Outcome Measure Information:
Title
Incidence of Treatment-Emergent Adverse Events
Description
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).
Time Frame
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
Title
Change in DNA methyltransferases expression. (DNMT)
Description
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).
Time Frame
Three months after study enrollment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ricardo Gama, MD, PHD
Organizational Affiliation
Barretos Cancer Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
André Lopes Carvalho, MD, PHD
Organizational Affiliation
Barretos Cancer Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Luciano de Souza Viana, MD, PHD
Organizational Affiliation
Barretos Cancer Hospital
Official's Role
Study Chair
Facility Information:
Facility Name
Barretos Cancer Hospital
City
Barretos
State/Province
São Paulo
ZIP/Postal Code
14784-400
Country
Brazil

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
As soon as we have results they will be shared.
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Chemoprevention of Head and Neck Squamous Cell Carcinoma (HNSCC) With Valproic Acid

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