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

NCT ID: NCT02608736

Last Updated: 2018-02-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-31
• Study Completion Date: 2017-07-31

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).

Conditions

Head and Neck Squamous Cell Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Valproic Acid

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

Group Type: EXPERIMENTAL

Valproic Acid

Intervention Type: DRUG

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.

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Divalproex; Depakene; Depacon; Depakote; Inert, not active

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Barretos Cancer Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ricardo Gama, MD, PHD

Role: PRINCIPAL_INVESTIGATOR

Barretos Cancer Hospital

André Lopes Carvalho, MD, PHD

Role: STUDY_DIRECTOR

Barretos Cancer Hospital

Luciano de Souza Viana, MD, PHD

Role: STUDY_CHAIR

Barretos Cancer Hospital

Locations

Barretos Cancer Hospital

Barretos, São Paulo, Brazil

Countries

Brazil

References

Brodie SA, Li G, El-Kommos A, Kang H, Ramalingam SS, Behera M, Gandhi K, Kowalski J, Sica GL, Khuri FR, Vertino PM, Brandes JC. Class I HDACs are mediators of smoke carcinogen-induced stabilization of DNMT1 and serve as promising targets for chemoprevention of lung cancer. Cancer Prev Res (Phila). 2014 Mar;7(3):351-61. doi: 10.1158/1940-6207.CAPR-13-0254. Epub 2014 Jan 17.

Reference Type: BACKGROUND

PMID: 24441677 (View on PubMed)

Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001 Dec 17;20(24):6969-78. doi: 10.1093/emboj/20.24.6969.

Reference Type: BACKGROUND

PMID: 11742974 (View on PubMed)

Gan CP, Hamid S, Hor SY, Zain RB, Ismail SM, Wan Mustafa WM, Teo SH, Saunders N, Cheong SC. Valproic acid: growth inhibition of head and neck cancer by induction of terminal differentiation and senescence. Head Neck. 2012 Mar;34(3):344-53. doi: 10.1002/hed.21734. Epub 2011 Mar 24.

Reference Type: BACKGROUND

PMID: 21438066 (View on PubMed)

Chavez-Blanco A, Segura-Pacheco B, Perez-Cardenas E, Taja-Chayeb L, Cetina L, Candelaria M, Cantu D, Gonzalez-Fierro A, Garcia-Lopez P, Zambrano P, Perez-Plasencia C, Cabrera G, Trejo-Becerril C, Angeles E, Duenas-Gonzalez A. Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study. Mol Cancer. 2005 Jul 7;4(1):22. doi: 10.1186/1476-4598-4-22.

Reference Type: BACKGROUND

PMID: 16001982 (View on PubMed)

Kang H, Gillespie TW, Goodman M, Brodie SA, Brandes M, Ribeiro M, Ramalingam SS, Shin DM, Khuri FR, Brandes JC. Long-term use of valproic acid in US veterans is associated with a reduced risk of smoking-related cases of head and neck cancer. Cancer. 2014 May 1;120(9):1394-400. doi: 10.1002/cncr.28479. Epub 2014 Mar 24.

Reference Type: BACKGROUND

PMID: 24664792 (View on PubMed)

Kuendgen A, Knipp S, Fox F, Strupp C, Hildebrandt B, Steidl C, Germing U, Haas R, Gattermann N. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol. 2005 Dec;84 Suppl 1:61-6. doi: 10.1007/s00277-005-0026-8.

Reference Type: BACKGROUND

PMID: 16270213 (View on PubMed)

Balbi A, Sottofattori E, Mazzei M, Sannita WG. Study of bioequivalence of magnesium and sodium valproates. J Pharm Biomed Anal. 1991;9(4):317-21. doi: 10.1016/0731-7085(91)80200-s.

Reference Type: BACKGROUND

PMID: 1911984 (View on PubMed)

Erlich RB, Rickwood D, Coman WB, Saunders NA, Guminski A. Valproic acid as a therapeutic agent for head and neck squamous cell carcinomas. Cancer Chemother Pharmacol. 2009 Feb;63(3):381-9. doi: 10.1007/s00280-008-0747-1. Epub 2008 Apr 9.

Reference Type: BACKGROUND

PMID: 18398612 (View on PubMed)

Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999 Jan;21(1):103-7. doi: 10.1038/5047.

Reference Type: BACKGROUND

PMID: 9916800 (View on PubMed)

Raffoux E, Cras A, Recher C, Boelle PY, de Labarthe A, Turlure P, Marolleau JP, Reman O, Gardin C, Victor M, Maury S, Rousselot P, Malfuson JV, Maarek O, Daniel MT, Fenaux P, Degos L, Chomienne C, Chevret S, Dombret H. Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome. Oncotarget. 2010 May;1(1):34-42. doi: 10.18632/oncotarget.106.

Reference Type: BACKGROUND

PMID: 21293051 (View on PubMed)

Kuendgen A, Bug G, Ottmann OG, Haase D, Schanz J, Hildebrandt B, Nachtkamp K, Neukirchen J, Dienst A, Haas R, Germing U, Gattermann N. Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid. Clin Epigenetics. 2011 Aug;2(2):389-99. doi: 10.1007/s13148-011-0031-9. Epub 2011 Apr 8.

Reference Type: BACKGROUND

PMID: 22704349 (View on PubMed)

Issa JP, Garcia-Manero G, Huang X, Cortes J, Ravandi F, Jabbour E, Borthakur G, Brandt M, Pierce S, Kantarjian HM. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015 Feb 15;121(4):556-61. doi: 10.1002/cncr.29085. Epub 2014 Oct 21.

Reference Type: BACKGROUND

PMID: 25336333 (View on PubMed)

Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, Cortes J, Wierda WG, Ouzounian S, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Garcia-Manero G. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007 Oct 1;110(7):2302-8. doi: 10.1182/blood-2007-03-078576. Epub 2007 Jun 27.

Reference Type: BACKGROUND

PMID: 17596541 (View on PubMed)

Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010 Jan;31(1):27-36. doi: 10.1093/carcin/bgp220. Epub 2009 Sep 13.

Reference Type: BACKGROUND

PMID: 19752007 (View on PubMed)

Duenas-Gonzalez A, Candelaria M, Perez-Plascencia C, Perez-Cardenas E, de la Cruz-Hernandez E, Herrera LA. Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors. Cancer Treat Rev. 2008 May;34(3):206-22. doi: 10.1016/j.ctrv.2007.11.003. Epub 2008 Jan 15.

Reference Type: BACKGROUND

PMID: 18226465 (View on PubMed)

Other Identifiers

BarretosCH - Head and Neck

Identifier Type: -

Identifier Source: org_study_id