Metastatic Colorectal CancerPhase 2NCT05694936
Combining Sodium Valproate With Standard-of-care EGFR (Epidermal Growth Factor Receptor) Monoclonal Antibody Treatment in Patients With Metastatic Colorectal Cancer
A Phase 2 study testing Sodium Valproate, Panitumumab and Cetuximab in people with Metastatic Colorectal Cancer, run by Australasian Gastro-Intestinal Trials Group at 12 sites in Australia.
Trial summary
The aim of this study is to determine the efficacy of combining the histone deacetylase (HDAC) inhibitor sodium valproate (VPA) with anti-EGFR monoclonal antibody (panitumumab or cetuximab) maintenance in the first-line treatment of patients with RAS wild type metastatic CRC. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Colorectal Cancer
- What is being tested?
- Sodium Valproate, Panitumumab and Cetuximab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 12 sitesAustralia
- Study dates
- 23 Jan 2023to Jun 2027
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years.
- Histological diagnosis of colorectal cancer.
- Metastatic colorectal cancer that is being treated with non-curative intent. This may be because the disease is anatomically not resectable, resection is contra-indicated for any reason, or the patient refuses resection.
- Measurable disease as assessed by CT scan (by RECIST 1.1).
- Evidence of RAS wild type status (KRAS exons 2, 3 and 4 and NRAS exons 2, 3, and 4) as assessed by the investigators' choice of testing laboratory.
- ECOG performance status 0, 1.
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- Suitable, as deemed by the investigator, for maintenance treatment with panitumumab or cetuximab alone or in combination with oral sodium valproate.
- Completed four months of first-line induction treatment with fluoropyrimidine-based chemotherapy (which may be intravenous or oral, in which case 15 weeks of treatment is required; and either alone or in combination with oxaliplatin or irinotecan) and anti-EGFR monoclonal antibody (panitumumab or cetuximab) without progressive disease.
- Prior palliative radiotherapy is allowed, provided that (i) no concurrent chemotherapy was administered, (ii) at least 2 weeks after completion of therapy has elapsed before enrolment, and (iii) any toxicities have resolved or are Grade 1. Prior fluoropyrimidine chemotherapy given concurrent with radiation as neoadjuvant treatment for rectal cancer is allowed.
- Adequate hepatic function with serum total bilirubin < x1.5 upper limit of normal range and ALT or AST < x3 upper limit of normal range.
- Adequate bone marrow function with platelets ≥ 80 X 109/L; neutrophils ≥ 1.5 X 109/L; haemoglobin ≥ 8g/dL.
- Adequate renal function, with calculated creatinine clearance ≥ 50 mL/min.
- Any abnormalities in magnesium are not > Grade 2. Any abnormalities in total calcium are not > Grade 1. Total calcium should be corrected for albumin level as per the institution's usual calculation method. Serum potassium levels should be above 4.0 mmol/L.
- Archival formalin-fixed paraffin embedded (FFPE) tumour tissue is available for storage and use by the central laboratory.
- Life expectancy of at least 12 weeks.
- Women and partners of women of childbearing potential must agree to use adequate contraception uninterrupted for the duration of receiving VPA, cetuximab and panitumumab, and for an additional 2 months after the last dose of cetuximab and 6 months after the last dose of panitumumab. Adequate contraceptive measures are barrier methods (condoms, diaphragm); oral, injectable, or implant birth control; or abstinence.
- Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
- Written informed consent including consent for donation of tumour tissue for biomarker studies and collection of peripheral blood for research.
Who cannot join
- BRAFV600E mutant CRC.
- CRC with HER2 IHC score of 3+. Note that IHC evaluation for HER2 amplification is required for determining eligibility. HER2 testing using ISH is not required.
- Prior chemotherapy before first-line induction chemotherapy. Exceptions are adjuvant chemotherapy which was given in association with (i) complete resection of primary colon or rectal cancer provided there is no clinical, radiological or biochemical evidence 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 lung provided there is no clinical, radiological or biochemical evidence of relapse for at least 6 months after completion of adjuvant treatment.
- History of life-threatening hypersensitivity reactions to panitumumab or cetuximab, or any product excipients of panitumumab or cetuximab.
- Known hypersensitivity to sodium valproate.
- Any other contraindication/s to sodium valproate including mitochondrial disorders and urea cycle disorders.
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- Pre-existing acute or chronic hepatic dysfunction or family history of severe hepatitis
- Patients with systemic lupus erythematosus are eligible, however the investigator should discuss the potential risk of immune disorders with the participant, which have been noted only exceptionally during the use of VPA.
- Patients with long QT syndrome, or QTc interval duration > 480 msec, or use of concomitant medications that significantly prolong the QTc interval.
- Prior or current treatment with HDAC inhibitor or compounds with HDAC inhibitor-like activity, 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) based HDAC inhibitors.
- Active treatment with sodium valproate for non-oncological conditions.
- Active epilepsy or convulsive conditions that require continuous use of anticonvulsants.
- History of interstitial lung disease or pulmonary fibrosis.
- Leptomeningeal disease as the only manifestation of malignancy.
- Untreated/active CNS metastases (i.e., progressing, requiring ongoing corticosteroids or anticonvulsants for symptom control).
- Patients with CNS metastases are eligible if they have previously been successfully treated with surgery and/or radiotherapy at least 8 weeks prior to cycle 1 day 1, have ceased taking all corticosteroids and/or anticonvulsants for at least 4 weeks and if imaging within 4 weeks of cycle 1 day 1 excludes any progression.
- 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, or any other cancer which was treated with curative intent > 2 years prior to randomisation and without evidence of relapse, are eligible.
- Active infection requiring systemic therapy and/or other concurrent uncontrolled medical conditions.
- Positive pregnancy test prior to the initiation of the study medications.
- History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate.
- Medical, psychiatric conditions or any other reason that, as assessed by the investigator, may compromise the patient's ability to give informed consent or to comply with the protocol-specified treatments and assessments.
Trial locations and contacts
12 sites in 1 country.
12 sites in 1 country
Australia12 sites
Queen Elizabeth Hospital
Adelaide, South Australia, 5000
Grampians Health
Ballarat Central, Victoria, 3350
Southern Adelaide Local Health Network Incorporated
Bedford Park, South Australia, 5042
Eastern Health
Box Hill, Victoria, 3128
Peninsula Health
Frankston, Victoria, 3199
Royal Brisbane and Women's Hospital
Herston, Queensland, 4029
Peter MacCallum Cancer Institute
Melbourne, Victoria, 3000
Austin Health
Melbourne, Victoria, 3084
Royal North Shore Hospital
Saint Leonards, New South Wales, 2065
St Vincent's Hospital Sydney
Sydney, New South Wales, 2010
South West Healthcare
Warrnambool, Victoria, 3280
Western Sydney Local Health District
Westmead, New South Wales, 2145
About this study
Official title: A Phase II Trial to Determine the Efficacy of Combining the HDAC Inhibitor Sodium Valproate With EGFR Monoclonal Antibody (Panitumumab or Cetuximab) Maintenance in the First-line Treatment of Patients With RAS Wild Type Metastatic Colorectal Cancer (VADER Study).
The aim of this study is to determine the efficacy of combining the histone deacetylase (HDAC) inhibitor sodium valproate (VPA) with anti-EGFR monoclonal antibody (panitumumab or cetuximab) maintenance in the first-line treatment of patients with RAS wild type metastatic CRC.
Read the detailed description
The primary objective is to evaluate progression free survival (PFS) in patients with RAS wild type metastatic CRC treated in the first-line with VPA plus panitumumab or cetuximab maintenance, or panitumumab or cetuximab maintenance alone.
The secondary objectives are (i) to evaluate overall survival (OS) and objective response rates (ORRs; RECIST v 1.1) in patients with RAS wild type metastatic CRC treated in the first-line with VPA plus panitumumab or cetuximab maintenance, and panitumumab or cetuximab maintenance alone; and (ii) to evaluate the safety (NCI CTCAE v5.0) of first-line maintenance treatment with VPA plus panitumumab or cetuximab, and panitumumab or cetuximab maintenance alone in patients with RAS wild type metastatic CRC.
The tertiary and exploratory objectives are:
- To evaluate Health-Related Quality of Life (EORTC QLQ-C30 and EQ-5D-5L) in patients with RAS wild type metastatic CRC treated in the first-line with VPA plus panitumumab or cetuximab maintenance, and panitumumab or cetuximab maintenance alone.
- Exploratory analyses including, but not limited to: (i) Determining whether changes in levels of histone acetylation in peripheral blood mononuclear cells (PBMCs) are associated with improved efficacy with VPA plus anti-EGFR monoclonal antibody maintenance treatment; and (ii) determining whether potential resistance-conferring mutations in circulating tumour DNA (ctDNA) are associated with efficacy outcomes in patients treated with anti-EGFR monoclonal antibody maintenance.
- Conditions
- Metastatic Colorectal Cancer
- Being tested
- Sodium Valproate, Panitumumab, Cetuximab
- Keywords
- RAS Wild type Metastatic Colorectal Cancer
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sodium ValproateDrug
Sodium valproate oral continuously in a twice daily dose (Initial dose of 600mg/d up-titrated to target daily dose of 20 mg/kg/d at Cycle 1 Day 13, then dose adjusted to maintain serum VPA levels within the target range of 50-100 μg/mL); Refer to arm description.
PanitumumabDrug
Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks; Refer to arm description.
CetuximabDrug
Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks; Refer to arm description.
| Study group | Role | What they receive |
|---|---|---|
| Experimental arm (n=60) | Experimental | Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks, with sodium valproate oral continuously in a twice daily dose (target daily dose of 20 mg/kg/d at Cycle 1 Day 13, then dose adjusted to maintain serum VPA levels within the target range of 50-100 μg/mL) Receives: Drug: Sodium Valproate; Drug: Panitumumab; Drug: Cetuximab |
| Control arm (n=30) | Active comparator | Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks Receives: Drug: Panitumumab; Drug: Cetuximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression free survival
Progression free survival (PFS) will be defined as the interval from date of registration or randomisation to the date of first evidence of disease progression (measured by RECIST v1.1 criteria) or death whichever occurs first, in each treatment arm.
Measured: 12 Months from randomisation
Secondary outcomes (3)
Overall Survival
Overall survival (OS) will be defined as the interval from date of registration or randomisation to date of death from any cause.
Measured: 12 Months from randomisation
Objective response rates (ORRs)
ORRs will be calculated as the proportion of participants in each arm who are assessed as having a complete or partial response measured by RECIST v1.1.
Measured: 12 Months from randomisation
Quantification of the incidence of treatment-emergent adverse events according to CTCAE V5.0
Safety of each treatment arm will be assessed by evaluating the number and severity (grade) of adverse events reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).
Measured: 12 Months from randomisation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2023
- Study start23 Jan 2023
- Primary completion21 Jan 2026
- Study completionJun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic Colorectal CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- Australasian Gastro-Intestinal Trials Group
- Sponsor type
- Research network
- Collaborators
- Olivia Newton-John Cancer Research Institute
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05694936
- Sponsor's protocol ID
- VADER
- Status last verified
- May 2026
- First submitted
- 8 Dec 2022
- Last updated
- 8 May 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Trial to Determine the Efficacy of Combining the HDAC Inhibitor Sodium Valproate With EGFR Monoclonal Antibody (Panitumumab or Cetuximab) Maintenance in the First-line Treatment of Patients With RAS Wild Type Metastatic Colorectal Cancer (VADER Study).
- ClinicalTrials.gov ID
- NCT05694936
- Acronym / sponsor ID
- VADER
- Conditions
- Metastatic Colorectal Cancer
- Keywords
- RAS Wild type Metastatic Colorectal Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 38 participants (actual)
- Lead sponsor
- Australasian Gastro-Intestinal Trials GroupResearch network
- Collaborators
- Olivia Newton-John Cancer Research Institute
- Study start
- 23 Jan 2023 (actual)
- Primary completion
- 21 Jan 2026 (actual)
- Study completion
- Jun 2027 (estimated)
- First posted
- 23 Jan 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of this study is to determine the efficacy of combining the histone deacetylase (HDAC) inhibitor sodium valproate (VPA) with anti-EGFR monoclonal antibody (panitumumab or cetuximab) maintenance in the first-line treatment of patients with RAS wild type metastatic CRC.
Detailed description
The primary objective is to evaluate progression free survival (PFS) in patients with RAS wild type metastatic CRC treated in the first-line with VPA plus panitumumab or cetuximab maintenance, or panitumumab or cetuximab maintenance alone.
The secondary objectives are (i) to evaluate overall survival (OS) and objective response rates (ORRs; RECIST v 1.1) in patients with RAS wild type metastatic CRC treated in the first-line with VPA plus panitumumab or cetuximab maintenance, and panitumumab or cetuximab maintenance alone; and (ii) to evaluate the safety (NCI CTCAE v5.0) of first-line maintenance treatment with VPA plus panitumumab or cetuximab, and panitumumab or cetuximab maintenance alone in patients with RAS wild type metastatic CRC.
The tertiary and exploratory objectives are:
- To evaluate Health-Related Quality of Life (EORTC QLQ-C30 and EQ-5D-5L) in patients with RAS wild type metastatic CRC treated in the first-line with VPA plus panitumumab or cetuximab maintenance, and panitumumab or cetuximab maintenance alone.
- Exploratory analyses including, but not limited to: (i) Determining whether changes in levels of histone acetylation in peripheral blood mononuclear cells (PBMCs) are associated with improved efficacy with VPA plus anti-EGFR monoclonal antibody maintenance treatment; and (ii) determining whether potential resistance-conferring mutations in circulating tumour DNA (ctDNA) are associated with efficacy outcomes in patients treated with anti-EGFR monoclonal antibody maintenance.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Experimental arm (n=60) | Experimental | Drug: Sodium Valproate, Drug: Panitumumab, Drug: CetuximabPanitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks, with sodium valproate oral continuously in a twice daily dose (target daily dose of 20 mg/kg/d at Cycle 1 Day 13, then dose adjusted to maintain serum VPA levels within the target range of 50-100 μg/mL) |
| Control arm (n=30) | Active comparator | Drug: Panitumumab, Drug: CetuximabPanitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- Age ≥ 18 years.
- Histological diagnosis of colorectal cancer.
- Metastatic colorectal cancer that is being treated with non-curative intent. This may be because the disease is anatomically not resectable, resection is contra-indicated for any reason, or the patient refuses resection.
- Measurable disease as assessed by CT scan (by RECIST 1.1).
- Evidence of RAS wild type status (KRAS exons 2, 3 and 4 and NRAS exons 2, 3, and 4) as assessed by the investigators' choice of testing laboratory.
Key exclusion criteria (22 listed)
- BRAFV600E mutant CRC.
- CRC with HER2 IHC score of 3+. Note that IHC evaluation for HER2 amplification is required for determining eligibility. HER2 testing using ISH is not required.
- Prior chemotherapy before first-line induction chemotherapy. Exceptions are adjuvant chemotherapy which was given in association with (i) complete resection of primary colon or rectal cancer provided there is no clinical, radiological or biochemical evidence 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 lung provided there is no clinical, radiological or biochemical evidence of relapse for at least 6 months after completion of adjuvant treatment.
- History of life-threatening hypersensitivity reactions to panitumumab or cetuximab, or any product excipients of panitumumab or cetuximab.
- Known hypersensitivity to sodium valproate.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sodium ValproateSodium valproate oral continuously in a twice daily dose (Initial dose of 600mg/d up-titrated to target daily dose of 20 mg/kg/d at Cycle 1 Day 13, then dose adjusted to maintain serum VPA levels within the target range of 50-100 μg/mL); Refer to arm description. | Drug | Experimental arm (n=60) |
| PanitumumabPanitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks; Refer to arm description. | Drug | Control arm (n=30), Experimental arm (n=60) |
| CetuximabPanitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks; Refer to arm description. | Drug | Control arm (n=30), Experimental arm (n=60) |
Primary outcome
Progression free survival
Time frame: 12 Months from randomisation
Progression free survival (PFS) will be defined as the interval from date of registration or randomisation to the date of first evidence of disease progression (measured by RECIST v1.1 criteria) or death whichever occurs first, in each treatment arm.
3 secondary outcomes
Overall Survival
Time frame: 12 Months from randomisation
Objective response rates (ORRs)
Time frame: 12 Months from randomisation
Quantification of the incidence of treatment-emergent adverse events according to CTCAE V5.0
Time frame: 12 Months from randomisation
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 May 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Sodium Valproate, Panitumumab and Cetuximab in people with Metastatic Colorectal Cancer, run by Australasian Gastro-Intestinal Trials Group at 12 sites in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 8 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression free survival (time frame: 12 Months from randomisation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 May 2026.