The investigators hypothesize that the epigenetic agent valproic acid improve the activity of anti-EGFR agents, prevent and revert the emergence of EGFR resistance, in a rechallenge setting.
Correlative mechanistic studies on tissue and blood samples, liquid biopsies, could identify potential biomarkers of efficacy and help understanding the evolutionary dynamics of tumors in response to therapy thus optimizing the treatment approach with a personalized anti- EGFR treatment strategy.
Written informed consent to study procedures and to correlative studies.
Either sex aged ≥ 18.
Histologically proven of colorectal adenocarcinoma.
Diagnosis of metastatic disease.
Prior malignancy within five years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
Any contraindication to panitumumab or irinotecan.
Not received immunotherapy if dMMR or MSI-H.
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.
Parallel
irinotecan
DrugAdministered at the dosage of 180 mg/m2 over 60 minutes
panitumumab
DrugAdministered as 60 minutes, or 90 minutes for doses over 1000 mg, intravenous infusion at the dosage of 6 mg/kg
Valproic Acid (VPA)
DrugVPA will be administered in each patient with a titration strategy to improve the compliance for the treatment, looking for a target serum level between 50 and 100 μg/mL that represents the recommended values for the treatment of epilepsy and also a useful concentration to produce the desired synergistic effect with chemotherapy based on preclinical studies. Administrated at the dosage of 500 mg/three times a day (after 7 days of gradual dose escalation).
Study Part 1 - Progression Free Survival rate at 16 weeks in the two arms.
Progression Free Survival rate at 16 weeks (PFS rate at 16-weeks) is defined as the rate of assessable patients alive and not progressed after 16 weeks from initiation of VICTORIA - Study Part 1 (i.e randomization) to the first documentation of objective disease progression by RECIST 1.1 criteria, or death due to any cause, whichever occurs first.
Study Part 1: Progression free survival (PFS)
Progression free survival (PFS) calculated as the time from randomization until the date of death from any cause until the date of the first observation of disease progression or death due to any cause, whichever occurs first. PFS will be censored at the time of the last available tumor assessment documenting absence of progressive disease for patients alive at the time of analysis.
Study Part 1 - Overall survival (OS)
Overall survival (OS) calculated as the time from randomization until the date of death from any cause. OS will be censored at the last date the patient was known to be alive for patients alive at the time of analysis.
Study Part 1: Objective Tumor Response Rate (ORR)
Objective Tumor Response Rate (ORR) assessed according to RECIST criteria 1.1, as the proportion of patients achieving complete or partial response relative to total enrolled patients.
Study Part 1: Disease Control Rate (DCR)
Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response.
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