Trial Title:
Combining Sodium Valproate With Standard-of-care EGFR (Epidermal Growth Factor Receptor) Monoclonal Antibody Treatment in Patients With Metastatic Colorectal Cancer
NCT ID:
NCT05694936
Condition:
Metastatic Colorectal Cancer
Conditions: Official terms:
Colorectal Neoplasms
Cetuximab
Panitumumab
Valproic Acid
Conditions: Keywords:
RAS Wild type Metastatic Colorectal Cancer
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Sodium Valproate
Description:
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.
Arm group label:
Experimental arm (n=60)
Intervention type:
Drug
Intervention name:
Panitumumab
Description:
Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks; Refer to
arm description.
Arm group label:
Control arm (n=30)
Arm group label:
Experimental arm (n=60)
Intervention type:
Drug
Intervention name:
Cetuximab
Description:
Panitumumab 6 mg/kg IV every 2 weeks or cetuximab 500 mg/m2 IV every 2 weeks; Refer to
arm description.
Arm group label:
Control arm (n=30)
Arm group label:
Experimental arm (n=60)
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.
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.
Criteria for eligibility:
Criteria:
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.
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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Royal North Shore Hospital
Address:
City:
Saint Leonards
Zip:
2065
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Amy Williams
Email:
amy.williams@health.nsw.gov.au
Facility:
Name:
Queen Elizabeth Hospital
Address:
City:
Adelaide
Zip:
5000
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Lynda Sok
Email:
lynda.sok@sa.gov.au
Facility:
Name:
Southern Adelaide Local Health Network Incorporated
Address:
City:
Bedford Park
Zip:
5042
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Alison Richards
Email:
alison.richards@sa.gov.au
Facility:
Name:
Eben-Marie Garzina
Address:
City:
Ballarat Central
Zip:
3350
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Eben-Marie Garzina
Email:
eben-marie.garzina@bhs.org.au
Facility:
Name:
Eastern Health
Address:
City:
Box Hill
Zip:
3128
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Karen Lim
Email:
karen.lim@monash.edu
Facility:
Name:
Peninsula Health
Address:
City:
Frankston
Zip:
3199
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Jade Rice
Email:
jrice@phcn.vic.gov.au
Facility:
Name:
Peter MacCallum Cancer Institute
Address:
City:
Melbourne
Zip:
3000
Country:
Australia
Status:
Recruiting
Contact:
Last name:
John Buen
Email:
PCCTU.MoncB@petermac.org
Facility:
Name:
Austin Health
Address:
City:
Melbourne
Zip:
3084
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Kirsten Remen
Email:
kirsten.remen@austin.org.au
Contact backup:
Last name:
Donna Haberl
Email:
donna.haberl@austin.org.au
Facility:
Name:
South West Healthcare
Address:
City:
Warrnambool
Zip:
3280
Country:
Australia
Status:
Recruiting
Contact:
Last name:
Lucy Leonard
Email:
swhct@swh.net.au
Start date:
January 23, 2023
Completion date:
September 2024
Lead sponsor:
Agency:
Australasian Gastro-Intestinal Trials Group
Agency class:
Other
Collaborator:
Agency:
Olivia Newton-John Cancer Research Institute
Agency class:
Other
Source:
Australasian Gastro-Intestinal Trials Group
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05694936
