Hepatocellular Carcinoma Clinical Trial
Official title:
Hepatic and Circulating microRNAs miR-221 and miR-222 Expression and Its Clinical Significance in Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma (HCC) is the most frequent primary tumour of the liver and is the
third cause of cancer-related mortality worldwide. Depending on the stage of the disease, the
treatment options are surgery, liver transplantation, chemotherapy or radiotherapy.
Recently, scientific research has focused on small molecules called microRNAs which are
produced by human cells and can be released in the blood. They have a role in cell
proliferation and are found to be dysregulated in different types of cancer.
It has been shown that microRNAs have a role in the development of HCC but it is unknown if
these molecules can be used as markers for diagnosis and survival in HCC.
In particular, microRNAs miR-221 and miR-222 are dysregulated in the tumoral tissues in about
80% of patients with HCC. This can be assessed on tissues from liver biopsies or surgical
specimens, both invasive approaches. Only few studies showed the presence of microRNAs in the
blood of patients with HCC but it is unknown if there is a correlation between tumoral tissue
expression and circulating levels.
The aim of this study is to evaluate if these two microRNAs are expressed not only in the
tumoral tissues but also in the blood from cancer patients, and in different amounts compared
to circulating levels in healthy individuals. A correlation between tumoral tissue and blood
levels will also be evaluated.
Should this evaluation show a strong correlation and reliability of circulating microRNAs in
the diagnosis and follow up of HCC, future clinical trials targeting these microRNAs and
their related pathways might benefit from this being adopted as conventional practice instead
of the need of assessing tissue levels from liver biopsies.
The results of this pilot study will bring preliminary results as a first step for future
analysis on a larger cohort of patients.
1. Background & Rationale Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer
worldwide, and is the third cause of cancer-related mortality.
Surgical resection remains the best curative treatment option for patients with clinical
Barcelona-Clinic Liver Cancer (BCLC) stage A disease and it has shown benefits even in
the more advanced stage B with multifocal disease or limited vascular invasion.
Despite curative treatments offering a 5-year survival rate of 50-70%, recurrence rates
at 5 years after surgery are as high as 70%. Therefore, more efforts are needed in order
to identify prognostic factors for recurrence and survival.
MicroRNAs are a class of small non-coding RNAs molecules, which act as key regulators of
cell proliferation, differentiation, apoptosis and embryonic development, finely tuning
gene expression at post-transcriptional level. They act as oncogenes or tumor
suppressors depending on the target genes. In HCC, it has been reported the upregulation
or downregulation of a few cluster of microRNAs, with a subsequent activation of
molecular networks such as b-catenin, Ras, TGF-b, JAK/STAT and creation of a highly
controlled feedback mechanism.
Their involvement in carcinogenesis represents an important area of investigation for
the development of their clinical applications: diagnostics, monitoring and
therapeutics. MicroRNA profiles can distinguish between normal and cancerous tissue,
identify tissue of origin and also discriminate different subtypes or specific oncogenic
abnormalities. Indeed, microRNA mis-expression patterns are more accurate in identifying
the origin of tumours that are otherwise difficult to be determined, suggesting that
tumours more clearly maintain a unique tissue microRNA expression profile.
MicroRNAs could also be useful as early diagnosis biomarkers for patient follow-up.
In liver tumorigenesis, the role of miR-221 and miR-222 has not been completely
elucidated. Previous studies showed that miR-221 was upregulated in 83% of HCC tumoral
samples when compared with matched cirrhotic tissue.
Increased expression of serum miR-221 was found in HCC patients compared to healthy
normal controls, which was associated with the presence of other poor prognostic factors
and with poorer outcomes after liver resection.
The extraction of microRNAs from liver samples is limited by the ability to resecting
the tumour or the possibility to perform a liver biopsy in each patient. On the
contrary, a blood sample is easy to be collected and stored for analysis. At present, it
has not been clearly established a correlation between the expression of miR-221 and
miR-222 in the liver tissue (tumoral and non tumoral) and the circulating miR-221 and
miR-222 levels.
The confirmation of this correlation, would allow identifying a cutoff of circulating
levels which could be used as a surrogate marker in order to include HCC patients in
phase 3 trials without the need for a liver biopsy, which is often contraindicated for
clinical reasons and according to guidelines.
This is a pilot study to evaluate the correlation between the overexpression of miR-221
and miR-222 in paired tumoral/non tumoral liver tissue and blood samples in patients
with HCC and to identify a cutoff for the circulating levels to use as a surrogate
marker in clinical trials.
This study therefore aims to evaluate if miR-221 and miR-222 expression in the blood
correlates with tissue expression and if the circulating levels could be used as a
surrogate of overexpression in the tumoral liver tissue.
Should this evaluation show a strong correlation and reliability of circulating miRNAs,
in the diagnosis and follow up of HCC, future clinical trials targeting these miRNAs and
their related pathways might benefit from this being adopted as conventional practice
instead of the need of assessing tissue levels from liver biopsies.
The trial will be conducted in compliance with the principles of the Declaration of
Helsinki, the principles of GCP and all (if any) applicable regulatory requirements are
essential.
NHS Grampian Biorepository will provide the anonymised samples to be used for this
study. NHS Grampian Biorepository already has ethical approval in place for these types
of studies. Research and Development approval will be sought.
2. Methods Blood samples from patients with HCC and from age-matched healthy controls,
stored in the National bio-repository Scotland, will be tested for circulating miR-221
and miR-222 expression by the means of Real Time Reverse Transcription Polymerase Chain
Reaction (RT-qPCR). Similarly, levels of miR-221 and miR-222 will be assessed in paired
cancer and healthy liver tissue form patients with HCC.
Sample analysis will take place in the Institute for Health and Wellbeing Research
laboratory at Robert Gordon University (RGU) - Aberdeen.
Results from the analysis of samples and quantification of microRNAs via RT-qPCR will be
carried out by the chief investigator along with the research team in the laboratory
facilities.
Samples will be analysed to assess miR-221 and miR-222 overexpression between tumoral
and non tumoral liver tissue and to assess the correlation between this and circulating
miR-221 and miR-222. Circulating levels will be compared to results from age-matched
healthy controls.
The custodian of the data generated by the study will be the Chief Investigator.
Samples will be stored in the laboratory facilities at RGU and only the chief
investigator and the research team will have access to.
Data generated by the study will be collected in a spreadsheet which will be bespoke and
held on the intranet with access restricted only to the CI and the research team.
Anonymised data on computer files will be stored on password-protected databases
accessible only to the study investigators.
All written files will be stored in locked filling cabinets within a secure store at
Robert Gordon University with the exception of consents which are stored by NHS Grampian
Biorepository.
The University of Aberdeen and NHS Grampian monitoring procedures will be followed.
At the end of the research the samples will be stored by research team pending ethical
approval for use in another project, whereas the data generated by the study will be
stored on password-protected databases accessible only to the study investigators.
3. Consent Process NHS Grampian Biorepository seek informed consent by patients for
collection of tissue samples and blood through a dedicated research nurse and the use of
a patient information sheet and a consent form which are part of the NHS Grampian
Biorepository documentation.
A consent will be obtained for all the samples used in this study according to the
Biorepository consent process.
4. Trial Flowchart
- Five frozen paired hepatic tumoral and non tumoral tissue and five frozen plasma
samples obtained from patients with HCC and stored in the National Bio-Repository
Scotland (HCC Group, HCC). Five voluntary age-matched healthy controls will be
recruited to relate the expression of circulating miRNAs (Plasma Control Group,
PCG).
- Paired frozen HCC tissue specimens and their adjacent non-cancerous normal liver
will be collected in RNA Stabilisation tubes and stored at -80C until further
analysis and miRNAs extraction as per protocol. The average size of the specimen
will be 2 by 10 mm in diameter.
- Blood samples collected from both HCC Group and PCG (8-10ml, into BD Vacutainer
K3-EDTA blood collection tubes) will be collected. All samples will be sent to
Bio-Repository for further processing and then analysis and miRNAs extraction as
per protocol.
- The results of miRNAs extraction from paired HCC/non-cancerous tissues will be
compared and from HCC Group plasma will be compared to the matched plasma of
controls (PCG Group).
;
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT04209491 -
Interest of the Intervention of a Nurse Coordinator in Complex Care Pathway
|
||
Completed |
NCT03963206 -
Cabozantinib toLERANCE Study in HepatoCellular Carcinoma (CLERANCE)
|
Phase 4 | |
Completed |
NCT03268499 -
TACE Emulsion Versus Suspension
|
Phase 2 | |
Recruiting |
NCT05044676 -
Immune Cells as a New Biomarker of Response in Patients Treated by Immunotherapy for Advanced Hepatocellular Carcinoma
|
||
Recruiting |
NCT05263830 -
Glypican-3 as a Prognostic Factor in Patients With Hepatocellular Carcinoma Treated by Immunotherapy
|
||
Recruiting |
NCT05095519 -
Hepatocellular Carcinoma Imaging Using PSMA PET/CT
|
Phase 2 | |
Recruiting |
NCT05497531 -
Pilot Comparing ctDNA IDV vs. SPV Sample in Pts Undergoing Biopsies for Hepatobiliary and Pancreatic Cancers
|
N/A | |
Completed |
NCT05068193 -
A Clinical Trial to Compare the Pharmacokinetics and Bioequivalence of "BR2008" With "BR2008-1" in Healthy Volunteers
|
Phase 1 | |
Active, not recruiting |
NCT03781934 -
A Study to Evaluate MIV-818 in Patients With Liver Cancer Manifestations
|
Phase 1/Phase 2 | |
Terminated |
NCT03655613 -
APL-501 or Nivolumab in Combination With APL-101 in Locally Advanced or Metastatic HCC and RCC
|
Phase 1/Phase 2 | |
Active, not recruiting |
NCT03170960 -
Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors
|
Phase 1/Phase 2 | |
Recruiting |
NCT04242199 -
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INCB099280 in Participants With Advanced Solid Tumors
|
Phase 1 | |
Completed |
NCT04401800 -
Preliminary Antitumor Activity, Safety and Tolerability of Tislelizumab in Combination With Lenvatinib for Hepatocellular Carcinoma
|
Phase 2 | |
Withdrawn |
NCT05418387 -
A Social Support Intervention to Improve Treatment Among Hispanic Kidney and Liver Cancer Patients in Arizona
|
N/A | |
Active, not recruiting |
NCT04039607 -
A Study of Nivolumab in Combination With Ipilimumab in Participants With Advanced Hepatocellular Carcinoma
|
Phase 3 | |
Terminated |
NCT03970616 -
A Study of Tivozanib in Combination With Durvalumab in Subjects With Advanced Hepatocellular Carcinoma
|
Phase 1/Phase 2 | |
Recruiting |
NCT06239155 -
A Phase I/II Study of AST-3424 in Subjects With Advanced Solid Tumors
|
Phase 1/Phase 2 | |
Recruiting |
NCT03642561 -
Evaluation the Treatment Outcome for RFA in Patients With BCLC Stage B HCC in Comparison With TACE
|
Phase 2/Phase 3 | |
Recruiting |
NCT04118114 -
Phase II Study of PRL3-ZUMAB in Advanced Solid Tumors
|
Phase 2 | |
Completed |
NCT03222076 -
Nivolumab With or Without Ipilimumab in Treating Patients With Resectable Liver Cancer
|
Phase 2 |