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Timisnar - Biomarkers Satellite Study (Timisnar-mirna) (TiMiSNAR-miRNA)

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ClinicalTrials.gov Identifier: NCT03962088
Recruitment Status : Recruiting
First Posted : May 23, 2019
Last Update Posted : May 23, 2019
Sponsor:
Information provided by (Responsible Party):
Igor Monsellato, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria

Brief Summary:

Neoadjuvant chemoradiotherapy (nCHT) followed by surgery is the mainstay treatment for locally advanced rectal cancer, leading to significant decrease in tumor size (downsizing) and a shift towards earlier disease stage in the primary tumor and lymph nodes (downstaging). Extensive histopathological work-up of the tumor specimen after surgery including tumor regression grading (TRG) and lymph node status (ypN) helped to visualize individual tumor sensitivity to CRT retrospectively. Since the response to nCHT is heterogeneous, however, valid biomarkers are needed to monitor tumor response. A relevant number of studies aimed to identify molecular markers retrieved from tumor tissue while the relevance of blood-based biomarkers is less stringent assessed.

As a potential alternative to CEA and ctDNA, microRNAs (miRNAs) are currently under investigation to serve as blood-based biomarkers. miRNAs are small, noncoding RNAs that regulate gene expression by post-transcriptional mRNA binding, which promotes the destabilization of target miRNAs. The target specificity of miRNAs is largely predetermined by their so-called "seed-sequence" (containing nucleotides at position 2-7 of the miRNA). They are highly conserved between species, stable and easy detectable even in small concentrations. They have been widely analyzed in physiological and pathological processes, and their expression is tissue specific.


Condition or disease Intervention/treatment
Rectal Cancer Diagnostic Test: miRNA

Detailed Description:

Neoadjuvant chemoradiotherapy (nCHT) followed by surgery is the mainstay treatment for locally advanced rectal cancer, leading to significant decrease in tumor size (downsizing) and a shift towards earlier disease stage in the primary tumor and lymph nodes (downstaging). Extensive histopathological work-up of the tumor specimen after surgery including tumor regression grading (TRG) and lymph node status (ypN) helped to visualize individual tumor sensitivity to CRT retrospectively. Since the response to nCHT is heterogeneous, however, valid biomarkers are needed to monitor tumor response. A relevant number of studies aimed to identify molecular markers retrieved from tumor tissue while the relevance of blood-based biomarkers is less stringent assessed.

Blood samples, i.e. Liquid Biopsy, however, offer several advantages:

  1. Taking blood samples is less invasive, less expensive, easy to schedule, and nearly without any severe complications.
  2. Blood samples are a source of fresh DNA and RNA, without modifications due to preservatives; especially in the case of rectal cancer, beyond intratumoral heterogeneity, tumor biopsies are in general accompanied by normal, adenomatous or stromal tissue. This contamination may affect results of molecular analyses
  3. Investigating blood from patients can account for molecular heterogeneity and surrogate for tumor burden since tumor-derived fragments or biomarkers are collected from all tumor cells in a patients' body through circulation.
  4. Liquid biopsy may offer both the possibility of dynamic monitoring under treatment and the possibility to assess disease activity even after pathologic complete response (pCR) or after resection of the tumor when no tissue is left for molecular analyses.

In clinical routines, to date, carcinoembryonic antigen (CEA) is established as a colorectal cancer (CRC) related tumor marker but is not recommended as a screening test for colorectal cancer. First, normal levels of CEA do not exclude the possibility of a colorectal cancer. Second, an elevated CEA is not categorically associated with CRC, or in the period of follow-up with disease progression. Circulating tumor DNA (ctDNA) represents nowadays, the main approach to monitor tumor burden and therapy resistance, to evaluate the presence of residual disease after potentially curative treatment and to monitor disease recurrence with high sensitivity and specificity.

As a potential alternative to CEA and ctDNA, microRNAs (miRNAs) are currently under investigation to serve as blood-based biomarkers. miRNAs are small, noncoding RNAs that regulate gene expression by post-transcriptional mRNA binding, which promotes the destabilization of target miRNAs. The target specificity of miRNAs is largely predetermined by their so-called "seed-sequence" (containing nucleotides at position 2-7 of the miRNA). They are highly conserved between species, stable and easy detectable even in small concentrations. They have been widely analyzed in physiological and pathological processes, and their expression is tissue specific.

To date, no screening approach to identify relevant miRNAs as biomarkers in blood of patients with rectal cancer was undertaken.


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Study Type : Observational
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Timing To Minimally Invasive Surgery After Neoadjuvant Chemoradiotherapy For Rectal Cancer: A Multicenter Randomized Controlled Trial - Biomarkers Satellite Study
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : April 1, 2023
Estimated Study Completion Date : April 1, 2023

Intervention Details:
  • Diagnostic Test: miRNA

    15 ml of whole blood samples are collected in Vacutainer tubes with spray-coated K2EDTA and stored at room temperature. To minimize the hemolysis and nucleic acids degradation, plasma separation undergoes within 2 h.

    Within 1 h, tubes are subjected to a first centrifugation step at 2200 x g and room temperature for 15 min. Plasma supernatants are transferred to 15 mL tubes, carefully avoiding contact with the lymphocytic ring, and tubes are centrifuged a second time at 3000 x g and RT for 10 min to remove cellular debris.

    Plasma samples are then collected into 1.5 mL cryovials and all the aliquots are stored at −80 °C.



Primary Outcome Measures :
  1. Change in expression levels of plasma miRNA [ Time Frame: 5 years ]
    the association of variation between preneoadjuvant and postneoadjuvant expression levels of miRNA with pCR


Secondary Outcome Measures :
  1. miRNA expression and surgery [ Time Frame: 5 years ]
    changes in expression levels of miRNA following complete surgical resection with disease-free survival

  2. miRNA expression and surveillance [ Time Frame: 5 years ]
    the relation between changes in miRNA during surveillance and tumor relapse


Biospecimen Retention:   Samples Without DNA
Total RNA, including miRNAs, are isolated using a commercial kit (miRNeasy Mini Kit, Qiagen, Hilden, Germany) according to the manufacturer's instructions. The RNA concentration is assessed using a spectrophotometer. The RNA results adequate for mRNA expression whenever its concentration is ≥30 ng/μL and its quality is acceptable if the ratio between the value of the absorbance (A) at 260 nm and the absorbance at 280 nm is ≥1.8, and the ratio between the value of absorbance (A) at 260 nm and the one at 230 nm is ≥2.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
All included patients in the TiMiSNAR Trial (already approved by local Ethical Committees on 8/5/2018 - NCT3465982) are supposed to undergo blood collection at the time of diagnosis, after neoadjuvant treatment, after 1 month from surgery and after adjuvant chemotherapy whenever indicated.
Criteria

Inclusion Criteria:

  • Age >18 years
  • cT3/4N0/+M0 confirmed on CT-scan, MRI (stratification for T3a-b-c-d)
  • Histologically-proven adenocarcinoma of the rectum
  • Eligible for a resective surgery with TME
  • Eligible for chemoradiation treatment

Exclusion Criteria:

  • Metastatic disease
  • Squamous carcinoma of the anal canal
  • Unable to complete neoadjuvant treatment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03962088


Contacts
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Contact: Igor Monsellato, PhD +390131206078 igor.monsellato@ospedale.al.it

Locations
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Italy
SS. Antonio e Biagio e Cesare Arrigo Recruiting
Alessandria, Italy
Contact: Igor Monsellato, PhD    +390131206078    igor.monsellato@ospedale.al.it   
Principal Investigator: Igor Monsellato, PhD         
Sub-Investigator: Sara Orecchia, PhD         
Sponsors and Collaborators
Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria

Additional Information:
Publications of Results:

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Responsible Party: Igor Monsellato, Principal Investigator, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria
ClinicalTrials.gov Identifier: NCT03962088     History of Changes
Other Study ID Numbers: A19
First Posted: May 23, 2019    Key Record Dates
Last Update Posted: May 23, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases