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

NCT02608736 | Completed Early Phase 1 DMC

• 1 other identifier: BarretosCH - Head and Neck
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

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.

Conditions

Head and Neck Squamous Cell Carcinoma

Keywords

head and neck squamous cell carcinoma; histone deacetylases; valproic acid; acetylation; chemoprevention; DNA methyltransferase; methylation

Outcome Measures

Primary Outcomes (1)

• 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).

  Three months after study enrollment

Secondary Outcomes (2)

• 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

• Change in DNA methyltransferases expression. (DNMT)

  Three months after study enrollment

Study Arms (2)

Valproic Acid

EXPERIMENTAL

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

Drug: Valproic Acid

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Valproic Acid 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.

Also known as: Divalproex, Depakene, Depacon, Depakote

Valproic Acid

Placebo 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.

Also known as: Inert, not active

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Barretos Cancer Hospital: lead

Study Sites (1)

Barretos Cancer Hospital

Barretos, São Paulo, 14784-400, Brazil

Location

Related Publications (15)

• 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.

  PMID: 24441677 BACKGROUND

• 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.

  PMID: 11742974 BACKGROUND

• 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.

  PMID: 21438066 BACKGROUND

• 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.

  PMID: 16001982 BACKGROUND

• 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.

  PMID: 24664792 BACKGROUND

• 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.

  PMID: 16270213 BACKGROUND

• 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.

  PMID: 1911984 BACKGROUND

• 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.

  PMID: 18398612 BACKGROUND

• 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.

  PMID: 9916800 BACKGROUND

• 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.

  PMID: 21293051 BACKGROUND

• 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.

  PMID: 22704349 BACKGROUND

• 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.

  PMID: 25336333 BACKGROUND

• 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.

  PMID: 17596541 BACKGROUND

• 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.

  PMID: 19752007 BACKGROUND

• 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.

  PMID: 18226465 BACKGROUND

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

Valproic Acid

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• Ricardo Gama, MD, PHD

  Barretos Cancer Hospital

  PRINCIPAL INVESTIGATOR

• André Lopes Carvalho, MD, PHD

  Barretos Cancer Hospital

  STUDY DIRECTOR

• Luciano de Souza Viana, MD, PHD

  Barretos Cancer Hospital

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 16, 2015
• First Posted: November 20, 2015
• Study Start: December 1, 2015
• Primary Completion: December 1, 2016
• Study Completion: July 1, 2017
• Last Updated: February 1, 2018

Record last verified: 2016-09

Data Sharing

• IPD Sharing: Will share

Locations

BR (1)