Clinical trial NCT02608736: Chemoprevention of Head and Neck Squamous Cell Carcinoma (HNSCC) With Valproic Acid
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
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Head and Neck Squamous Cell Carcinoma
Keywords: head and neck squamous cell carcinoma
histone deacetylases
valproic acid
acetylation
chemoprevention
DNA methyltransferase
methylation
Lead sponsor: Barretos Cancer Hospital
Sponsor class: OTHER
First posted: 2015-11-20
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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).

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.

Primary outcomes:
measure: Changes in protein or histone acetylation
timeFrame: Three months after study enrollment
Secondary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: 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
measure: Change in DNA methyltransferases expression. (DNMT)
timeFrame: Three months after study enrollment
Other outcomes:
Locations:
city: Barretos
country: Brazil
facility: Barretos Cancer Hospital
state: São Paulo
Study officials:
affiliation: Barretos Cancer Hospital
name: Ricardo Gama, MD, PHD
role: PRINCIPAL_INVESTIGATOR
affiliation: Barretos Cancer Hospital
name: André Lopes Carvalho, MD, PHD
role: STUDY_DIRECTOR
affiliation: Barretos Cancer Hospital
name: Luciano de Souza Viana, MD, PHD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.