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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05694936




Registration number
NCT05694936
Ethics application status
Date submitted
8/12/2022
Date registered
23/01/2023

Titles & IDs
Public title
Combining Sodium Valproate With Standard-of-care EGFR (Epidermal Growth Factor Receptor) Monoclonal Antibody Treatment in Patients With Metastatic Colorectal Cancer
Scientific title
A Phase II Randomised Controlled 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 (CRC)
Secondary ID [1] 0 0
VADER
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Colorectal Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Sodium Valproate
Treatment: Drugs - Panitumumab
Treatment: Drugs - Cetuximab

Experimental: Experimental arm (n=60) - 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)

Active comparator: Control arm (n=30) - Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks


Treatment: Drugs: Sodium Valproate
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.

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

Treatment: Drugs: Cetuximab
Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks; Refer to arm description.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression free survival
Timepoint [1] 0 0
12 Months from randomisation
Secondary outcome [1] 0 0
Overall Survival
Timepoint [1] 0 0
12 Months from randomisation
Secondary outcome [2] 0 0
Objective response rates (ORRs)
Timepoint [2] 0 0
12 Months from randomisation
Secondary outcome [3] 0 0
Quantification of the incidence of treatment-emergent adverse events according to CTCAE V5.0
Timepoint [3] 0 0
12 Months from randomisation

Eligibility
Key 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 may be because the disease is anatomically not resectable, resection is contra-indicated for 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) as assessed 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 or cetuximab alone or in combination with oral sodium valproate.
8. 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.
9. 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.
10. Adequate hepatic function with serum total bilirubin < x1.5 upper limit of normal range 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 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.
14. Archival formalin-fixed paraffin embedded (FFPE) tumour tissue is available for storage 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 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.
17. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
18. Written informed consent including consent for donation of tumour tissue for biomarker studies and collection of peripheral blood for research.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. BRAFV600E mutant CRC.
2. 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.
3. 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.
4. History of life-threatening hypersensitivity reactions to panitumumab or cetuximab, or any product excipients of panitumumab or cetuximab.
5. Known hypersensitivity to sodium valproate.
6. Any other contraindication/s to sodium valproate including mitochondrial disorders and urea cycle disorders.
7. Pre-existing acute or chronic hepatic dysfunction or family history of severe hepatitis
8. 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.
9. Patients with long QT syndrome, or QTc interval duration > 480 msec, or use of concomitant medications that significantly prolong the QTc interval.
10. 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.
11. Active treatment with sodium valproate for non-oncological conditions.
12. Active epilepsy or convulsive conditions that require continuous use of anticonvulsants.
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 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.
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, or any other cancer which was treated with curative intent > 2 years prior to randomisation and without evidence of relapse, are eligible.
17. Active infection requiring systemic therapy and/or other concurrent uncontrolled medical 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 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.
20. 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
23/01/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/09/2024
Actual
Sample size
Target
90
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 0 0
Royal North Shore Hospital - Saint Leonards
Recruitment hospital [2] 0 0
Queen Elizabeth Hospital - Adelaide
Recruitment hospital [3] 0 0
Southern Adelaide Local Health Network Incorporated - Bedford Park
Recruitment hospital [4] 0 0
Eben-Marie Garzina - Ballarat Central
Recruitment hospital [5] 0 0
Eastern Health - Box Hill
Recruitment hospital [6] 0 0
Peninsula Health - Frankston
Recruitment hospital [7] 0 0
Peter MacCallum Cancer Institute - Melbourne
Recruitment hospital [8] 0 0
Austin Health - Melbourne
Recruitment hospital [9] 0 0
South West Healthcare - Warrnambool
Recruitment postcode(s) [1] 0 0
2065 - Saint Leonards
Recruitment postcode(s) [2] 0 0
5000 - Adelaide
Recruitment postcode(s) [3] 0 0
5042 - Bedford Park
Recruitment postcode(s) [4] 0 0
3350 - Ballarat Central
Recruitment postcode(s) [5] 0 0
3128 - Box Hill
Recruitment postcode(s) [6] 0 0
3199 - Frankston
Recruitment postcode(s) [7] 0 0
3000 - Melbourne
Recruitment postcode(s) [8] 0 0
3084 - Melbourne
Recruitment postcode(s) [9] 0 0
3280 - Warrnambool

Funding & Sponsors
Primary sponsor type
Other
Name
Australasian Gastro-Intestinal Trials Group
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Olivia Newton-John Cancer Research Institute
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Sukanya Sathyamurthie
Address 0 0
Country 0 0
Phone 0 0
+61 2 7208 2719
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT05694936