Combining Sodium Valproate With Standard-of-care EGFR (Epidermal Growth Factor Receptor) Monoclonal Antibody Treatment in Patients With Metastatic Colorectal Cancer

Inclusion Criteria:

1. Age ≥ 18 years.
2. Histological diagnosis of colorectal cancer.
3. Metastatic colorectal cancer that is being treated with non-curative intent. This maybe because the disease is anatomically not resectable, resection is contra-indicatedfor any reason, or the patient refuses resection.
4. Measurable disease as assessed by CT scan (by RECIST 1.1).
5. Evidence of RAS wild type status (KRAS exons 2, 3 and 4 and NRAS exons 2, 3, and 4) asassessed by the investigators' choice of testing laboratory.
6. ECOG performance status 0, 1.
7. Suitable, as deemed by the investigator, for maintenance treatment with panitumumab orcetuximab alone or in combination with oral sodium valproate.
8. Completed four months of first-line induction treatment with fluoropyrimidine-basedchemotherapy (which may be intravenous or oral, in which case 15 weeks of treatment isrequired; and either alone or in combination with oxaliplatin or irinotecan) andanti-EGFR monoclonal antibody (panitumumab or cetuximab) without progressive disease.
9. Prior palliative radiotherapy is allowed, provided that (i) no concurrent chemotherapywas administered, (ii) at least 2 weeks after completion of therapy has elapsed beforeenrolment, and (iii) any toxicities have resolved or are Grade 1. Priorfluoropyrimidine chemotherapy given concurrent with radiation as neoadjuvant treatmentfor rectal cancer is allowed.
10. Adequate hepatic function with serum total bilirubin < x1.5 upper limit of normalrange and ALT or AST < x3 upper limit of normal range.
11. Adequate bone marrow function with platelets ≥ 80 X 109/L; neutrophils ≥ 1.5 X 109/L;haemoglobin ≥ 8g/dL.
12. Adequate renal function, with calculated creatinine clearance ≥ 50 mL/min.
13. Any abnormalities in magnesium are not > Grade 2. Any abnormalities in total calciumare not > Grade 1. Total calcium should be corrected for albumin level as per theinstitution's usual calculation method. Serum potassium levels should be above 4.0mmol/L.
14. Archival formalin-fixed paraffin embedded (FFPE) tumour tissue is available forstorage and use by the central laboratory.
15. Life expectancy of at least 12 weeks.
16. Women and partners of women of childbearing potential must agree to use adequatecontraception uninterrupted for the duration of receiving VPA, cetuximab andpanitumumab, and for an additional 2 months after the last dose of cetuximab and 6months after the last dose of panitumumab. Adequate contraceptive measures are barriermethods (condoms, diaphragm); oral, injectable, or implant birth control; orabstinence.
17. Willing and able to comply with all study requirements, including treatment, timingand/or nature of required assessments.
18. Written informed consent including consent for donation of tumour tissue for biomarkerstudies and collection of peripheral blood for research.

Exclusion Criteria:

1. BRAFV600E mutant CRC.
2. CRC with HER2 IHC score of 3+. Note that IHC evaluation for HER2 amplification isrequired for determining eligibility. HER2 testing using ISH is not required.
3. Prior chemotherapy before first-line induction chemotherapy. Exceptions are adjuvantchemotherapy which was given in association with (i) complete resection of primarycolon or rectal cancer provided there is no clinical, radiological or biochemicalevidence of relapse for at least 6 months after completion of adjuvant treatment,and/or (ii) complete resection of limited colorectal metastases to liver and/or lungprovided there is no clinical, radiological or biochemical evidence of relapse for atleast 6 months after completion of adjuvant treatment.
4. History of life-threatening hypersensitivity reactions to panitumumab or cetuximab, orany product excipients of panitumumab or cetuximab.
5. Known hypersensitivity to sodium valproate.
6. Any other contraindication/s to sodium valproate including mitochondrial disorders andurea cycle disorders.
7. Pre-existing acute or chronic hepatic dysfunction or family history of severehepatitis
8. Patients with systemic lupus erythematosus are eligible, however the investigatorshould discuss the potential risk of immune disorders with the participant, which havebeen noted only exceptionally during the use of VPA.
9. Patients with long QT syndrome, or QTc interval duration > 480 msec, or use ofconcomitant medications that significantly prolong the QTc interval.
10. Prior or current treatment with HDAC inhibitor or compounds with HDAC inhibitor-likeactivity, including hydroxamic acid (e.g vorinostat/zolinza, panobinostat/farydak.Belinostat/beleodaq), benzamide (tucidinostat/epidaza/chidamide), cyclic tetrapeptide (Romidepsin/Istodax) or carboxylic acid (e.g sodium valproate, phenylbutyrate) basedHDAC inhibitors.
11. Active treatment with sodium valproate for non-oncological conditions.
12. Active epilepsy or convulsive conditions that require continuous use ofanticonvulsants.
13. History of interstitial lung disease or pulmonary fibrosis.
14. Leptomeningeal disease as the only manifestation of malignancy.
15. Untreated/active CNS metastases (i.e., progressing, requiring ongoing corticosteroidsor anticonvulsants for symptom control). Patients with CNS metastases are eligible if they have previously been successfullytreated with surgery and/or radiotherapy at least 8 weeks prior to cycle 1 day 1, haveceased taking all corticosteroids and/or anticonvulsants for at least 4 weeks and ifimaging within 4 weeks of cycle 1 day 1 excludes any progression.
16. Invasive malignant disease, other than CRC, diagnosed within 2 years of randomisation. Patients with non-melanotic skin cancer, carcinoma in situ of the uterine cervix, orany other cancer which was treated with curative intent > 2 years prior torandomisation and without evidence of relapse, are eligible.
17. Active infection requiring systemic therapy and/or other concurrent uncontrolledmedical conditions.
18. Positive pregnancy test prior to the initiation of the study medications.
19. History or current evidence of any condition, therapy, or laboratory abnormality thatmight confound the results of the trial, interfere with the subject's participationfor the full duration of the trial, or is not in the best interest of the subject toparticipate.
20. Medical, psychiatric conditions or any other reason that, as assessed by theinvestigator, may compromise the patient's ability to give informed consent or tocomply with the protocol-specified treatments and assessments.