Valproic Acid Plus Cisplatin and Cetuximab in Recurrent and/or Metastatic Squamous Cell Carcinoma of Head and Neck

Study Overview
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Brief Summary
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V-CHANCE is a phase 2, trial exploring the feasibility and the activity of valproic acid (VPA) in combination with the standard cisplatin-cetuximab combination in patients with recurrent/metastatic squamous cell carcinoma of the head and neck, never treated with first-line chemotherapy. The study includes an explorative analysis of the potential prognostic or predictive role of several biomarkers with the aim of improving the knowledge of the mechanisms by which VPA enhances chemotherapy effect and of identifying early predictors of treatment response/resistance.

Official Title
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Preclinical and Clinical Study of Valproic Acid Plus Cisplatin and Cetuximab in Recurrent and/or Metastatic Squamous Cell Carcinoma of Head and Neck

Conditions
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Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: Valproic Acid
* Drug: Cisplatin
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven squamous cell carcinoma of head and neck with exclusion of the nasopharynx First-line recurrent and/or metastatic disease No prior chemotherapy except for chemoradiation or induction chemotherapy followed by local treatment given in the context of a curative strategy. age> 18 years ECOG Performance Status ≤1 Life expectancy at least 3 months at study entrance Normal bone marrow reserve (absolute neutrophil count > 1500/mm3; platelets > 100000/mm3; haemoglobin> 9 g/dl) Normal hepatic function (total serum bilirubin < 1.5 x upper limit of normal; liver transaminases < 3 x upper limit of normal) Normal renal function (serum creatinine < 1,25 x upper limit of normal and creatinine clearance > 60 ml/min). Normal cardiac function (assessed by ECG and echocardiography with ejection fraction > 50%) Effective contraception for both male and female patients if the risk of conception exist Signed written informed consent Exclusion Criteria: Concomitant treatment with other experimental drugs. Brain metastases (CT scan or MRI required only in case of clinical suspicion of CNS metastases) Non squamous cell histology Any concurrent malignancy. Patient with a previous malignancy but without evidence of disease for 5 years will be allowed to enter the trial. History of myocardial infarction within the last 12 months ECOG PS ≥ 2 Significant cardiovascular comorbidity (e.g. myocardial infarction, superior vena cava [SVC] syndrome, patients with an ejection fraction of <50%) or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia. History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Patients with long QT-syndrome or QTc interval duration > 480 msec or concomitant medication with drugs prolonging QTc. HIV positive patients Patients who cannot take oral medication, who require intravenous feeding, have had prior surgical procedures affecting absorption, or have active peptic ulcer disease. Known or suspected hypersensitivity to any of the study drugs. Patients who have had prior treatment with an HDAC inhibitor and patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid. Major surgical procedure within 28 days prior to study treatment start. Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline (postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential)l. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: valproic acid plus cisplatin and cetuximab<br> | Drug: Valproic Acid<br>* Treatment will be administered orally starting at day -14, with 500 mg slow releasing tablet at evening. Thereafter, the dose will be increased also using 300 mg tablets until reaching 1500 mg on day -1. The titration strategy is to reach a target VPA serum level of 50-100 μg/ml.<br>Drug: Cisplatin<br>* administered intravenously at dose of 75 mg/m2 given every three weeks for 6 cycles<br>Drug: Cetuximab<br>* administered intravenously at induction dose of 400 mg/m2 followed by maintenance doses of 250 mg/m2 given weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with an objective response | Response will be assessed according to RECIST v1.1 criteria | up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival |  | up to 6 years | 
| time to tumor progression |  | up to 6 years | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 |  | up to 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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head and neck cancer, valproic acid, recurrent, metastatic