title: Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial.
abstract: Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to down regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition (EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic disorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may be to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the possible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR.
  
  
  
  V-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell carcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration of cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from day -14 with a titration strategy in each patient (target serum level of 50-100 μg/ml). Primary end point is the objective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size, calculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit for rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18 responses. Secondary endpoints are time to progression, duration of response, overall survival, safety. Objectives of the translational study are the evaluation on tumor samples of markers of treatment efficacy/resistance (i.e. γH2AX, p21/WAF, RAD51, XRCC1, EGFR, p-EGFR, Ki-67) and specific markers of VPA HDAC inhibitory activity (histones and proteins acetylation, Histone deacetylase isoforms) as well as valproate test, histones and proteins acetylation of peripheral blood mononuclear cell, tested on blood samples at baseline and at different time points during treatment.
  
  
  
  Overall, this study could provide a less toxic and more effective first-line chemotherapy regimen in patients with recurrent/metastatic squamous cell carcinoma of the head and neck by demonstrating the feasibility and efficacy of cisplatin/cetuximab plus valproic acid. Moreover, correlative studies could help to identify responder patients, and will add insights in the mechanism of the synergistic interaction between these agents.
  
  
  
  2014-001523-69 TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02624128.
authors.affiliation: Head and Neck Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy. f.caponigro@istitutotumori.na.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Caponigro
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Di Gennaro
authors.affiliation: Head and neck Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Ionna
authors.affiliation: Head and neck Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Longo
authors.affiliation: Head and neck Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Aversa
authors.affiliation: Head and neck Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Pavone
authors.affiliation: Head and neck Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Maglione
authors.affiliation: Melanoma and soft tissue Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Marzo
authors.affiliation: Radiotherapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Muto
authors.affiliation: Clinical Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Ernesta
authors.initials: E
authors.lastname: Cavalcanti
authors.affiliation: Radiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Petrillo
authors.affiliation: Radiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sandomenico
authors.affiliation: Pharmacy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Maiolino
authors.affiliation: Pharmacy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: D'Aniello
authors.affiliation: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.affiliation: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: De Cecio
authors.affiliation: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Nunzia Simona
authors.initials: NS
authors.lastname: Losito
authors.affiliation: Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
authors.affiliation: Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Trotta
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Andrea Ilaria
authors.initials: AI
authors.lastname: Zotti
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bruzzese
authors.affiliation: Head and Neck Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Daponte
authors.affiliation: Head and Neck Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Calogero
authors.affiliation: Head and Neck Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Montano
authors.affiliation: Head and Neck Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Pontone
authors.affiliation: Scientific Direction, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: De Feo
authors.affiliation: Head and Neck Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy.|Present Address: Medical Oncology Unit, POC SS Annunziata, Taranto, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perri
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G. Pascale," IRCCS, Naples, Italy. a.budillon@istitutotumori.na.it.
authors.forename: Alfredo
authors.identifier: 0000-0001-6631-3550
authors.initials: A
authors.lastname: Budillon
mesh_terms: D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D000068818:Cetuximab / Q000008:administration & dosage* / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D000077195:Squamous Cell Carcinoma of Head and Neck; D016019:Survival Analysis; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D014635:Valproic Acid; D000068818:Cetuximab; D002945:Cisplatin
keywords: Cetuximab; Cisplatin; Head and Neck cancer; Histone deacetylase inhibitor; Valproic acid