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

NCT05694936 | Recruiting Phase 2

• 1 other identifier: VADER
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 11

Brief 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.

Conditions

Metastatic Colorectal Cancer

Keywords

RAS Wild type Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• 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.

  12 Months from randomisation

Secondary Outcomes (3)

• Overall Survival

  12 Months from randomisation

• Objective response rates (ORRs)

  12 Months from randomisation

• Quantification of the incidence of treatment-emergent adverse events according to CTCAE V5.0

  12 Months from randomisation

Other Outcomes (4)

• Health-related quality of life (EORTC QLQ-C30)

  12 Months from randomisation

• Health-related quality of life (EQ-5D-5L)

  12 Months from radomisation

• Quantification of histone acetylation levels in peripheral blood mononuclear cells (PBMCs)

  12 Months from radomisation

Study Arms (2)

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)

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

Drug: Panitumumab; Drug: Cetuximab

Interventions

Sodium Valproate DRUG

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.

Experimental arm (n=60)

Panitumumab DRUG

Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks; Refer to arm description.

Control arm (n=30); Experimental arm (n=60)

Cetuximab DRUG

Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks; Refer to arm description.

Control arm (n=30); Experimental arm (n=60)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• Australasian Gastro-Intestinal Trials Group: lead
• Olivia Newton-John Cancer Research Institute: collaborator

Study Sites (11)

Royal North Shore Hospital

Saint Leonards, New South Wales, 2065, Australia

RECRUITING

Western Sydney Local Health District

Westmead, New South Wales, 2145, Australia

RECRUITING

Royal Brisbane and Women's Hospital

Herston, Queensland, 4029, Australia

RECRUITING

Queen Elizabeth Hospital

Adelaide, South Australia, 5000, Australia

RECRUITING

Southern Adelaide Local Health Network Incorporated

Bedford Park, South Australia, 5042, Australia

RECRUITING

Grampians Health

Ballarat Central, Victoria, 3350, Australia

RECRUITING

Eastern Health

Box Hill, Victoria, 3128, Australia

RECRUITING

Peninsula Health

Frankston, Victoria, 3199, Australia

RECRUITING

Peter MacCallum Cancer Institute

Melbourne, Victoria, 3000, Australia

RECRUITING

Austin Health

Melbourne, Victoria, 3084, Australia

RECRUITING

South West Healthcare

Warrnambool, Victoria, 3280, Australia

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Valproic Acid; Panitumumab; Cetuximab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

Clinical Project Manager

CONTACT

03 9496 3088; trials@onjcri.org.au

Miriam Roesner

CONTACT

+61 2 7208 2727; miriam@gicancer.org.au

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 8, 2022
• First Posted: January 23, 2023
• Study Start: January 23, 2023
• Primary Completion: April 30, 2026
• Study Completion (Estimated): June 1, 2027
• Last Updated: September 18, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

AU (11)