Inclusion Criteria (Study Part 1):
1. Written informed consent to study procedures and to correlative studies.
2. Either sex aged ≥ 18.
3. Histologically proven of colorectal adenocarcinoma.
4. Diagnosis of metastatic disease.
5. RAS/BRAF wild-type status at initial diagnosis assessed at local centers according with a validated method defined by EMA and known MMR/MSI status
6. RAS (NRAS and KRAS exon 2,3 and 4) and BRAF wild-type in liquid biopsy at study entry (according to central testing).
7. Patient candidate to anti-EGFR rechallenge therapy with panitumumab and irinotecan as clinical practice; Efficacy of anti-EGFR drug in any line of treatment with a major response achieved (i.e. complete or partial response according to RECIST criteria v1.1) or stable disease ≥ 6 months and received a subsequent line of therapy upon progression.
a. Note. Patients must have received at least 2 lines of treatment. Previous treatment with regorafenib, trifluridine/tipiracile, trifluridine/tipiracile + bevacizumab or fruquintinib is allowed. Previous rechallenge with anti-EGFR MoAb is NOT allowed. Adjuvant treatment will be considered as one line of therapy in case of progression within 6 months from the last dose of treatment.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry.
9. Imaging-documented measurable disease, according to RECIST 1.1 criteria.
10. Estimated life expectancy of more than 12 weeks
11. Adequate bone marrow hematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL.
12. Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 2 (in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5 X ULN.
13. Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula).
14. Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range.
Exclusion Criteria (Study Part 1):
1. 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.
2. Any contraindication to panitumumab or irinotecan.
3. Not received immunotherapy if dMMR or MSI-H.
4. 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.
5. Major surgical intervention within 4 weeks prior to enrollment.
6. Pregnancy and breast-feeding.
7. Any brain metastasis.
8. Patients with long QT-syndrome or QTc interval duration \> 480 msec or concomitant medication with drugs prolonging QTc .
9. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study.
10. History of poor co-operation, non-compliance with medical treatment, unreliability or any condition that may impair the patient's understanding of the Informed consent form.
11. Participation in any interventional drug or medical device study within 30 days prior to treatment start.
12. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.
13. History of interstitial pneumonitis or pulmonary fibrosis.
14. History of corneal perforation or ulceration keratitis.
15. Hypersensitivity to valproic acid or any of listed excipients.
16. Acute hepatitis or chronic hepatitis.
17. Personal or familial anamnesis of severe hepatopathy.
18. History of Hepatic porphyria
19. Known coagulation disorders.
20. Known Polymerase-gamma (POLG) mitochondrial mutation (e.g. Alpers-Huttenlocher Syndrome).
21. Known urea cycle disorders.
* Inclusion Criteria (Study Part 2):
1\. Have provided written informed consent to study procedures and to correlative studies.
2\. Enrolled in VICTORIA - Study Part 1 and randomized to ARM A (control arm) 3. Progressed to treatment within ARM A (control arm). 4. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry.
5\. Imaging-documented measurable disease, according to RECIST 1.1 criteria. 6. Estimated life expectancy of more than 12 weeks. 7. Adequate bone marrow hematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL. 8. Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 2 (in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5 X ULN. 9. Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula). 10. Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range.
-Exclusion Criteria (Study Part 2):
1. Did not receive a subsequent line of therapy upon progression to ARM A.
2. Any brain metastasis.
3. Pregnancy and breast-feeding.
4. Serious Adverse events with panitumumab or irinotecan, leading to treatment interruption and discontinuation.
5. Patients with long QT-syndrome or QTc interval duration \> 480 msec or concomitant medication with drugs prolonging QTc
6. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study.
7. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.
