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Rectal CancerTiMiSNAR-miRNANCT03962088

Timisnar - Biomarkers Substudy (Timisnar-mirna)

An observational study of Rectal Cancer, run by Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria at 1 site in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Rectal Cancer
What is being tested?
miRNA
How many people
200 participants
Where
1 siteItaly
Study dates
1 Apr 2019to 1 Apr 2025
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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.

Who may be able to join

  • 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

Who cannot join

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

Trial locations and contacts

1 site in 1 country.

Italy1 site, 1 recruiting
  • SS. Antonio e Biagio e Cesare Arrigo

    Alessandria

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

    Igor Monsellato, PhD

    Recruiting

Other trials in Italy

About this study

Official title: Timing To Minimally Invasive Surgery After Neoadjuvant Chemoradiotherapy For Rectal Cancer: A Multicenter Randomized Controlled Trial - Biomarkers SubStudy

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.

Read the 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.

Conditions
Rectal Cancer
Being tested
miRNA
Medical subject headings
Rectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • miRNADiagnostic test

    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.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in expression levels of plasma miRNA

    the association of variation between preneoadjuvant and postneoadjuvant expression levels of miRNA with pCR

    Measured: 5 years

Secondary outcomes (2)
  1. miRNA expression and surgery

    changes in expression levels of miRNA following complete surgical resection with disease-free survival

    Measured: 5 years

  2. miRNA expression and surveillance

    the relation between changes in miRNA during surveillance and tumor relapse

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 May 2019
  2. Study start1 Apr 2019
  3. Primary completion1 Apr 2025 (estimated)
  4. Study completion1 Apr 2025 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
200 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03962088
Sponsor's protocol ID
A19
Acronym
TiMiSNAR-miRNA
Status last verified
Apr 2024
First submitted
21 May 2019
Last updated
16 Apr 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Yu J, Li N, Wang X, Ren H, Wang W, Wang S, Song Y, Liu Y, Li Y, Zhou X, Luo A, Liu Z, Jin J. Circulating serum microRNA-345 correlates with unfavorable pathological response to preoperative chemoradiotherapy in locally advanced rectal cancer. Oncotarget. 2016 Sep 27;7(39):64233-64243. doi: 10.18632/oncotarget.11649.

    PubMed 27572313
  • Dayde D, Tanaka I, Jain R, Tai MC, Taguchi A. Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer. Int J Mol Sci. 2017 Mar 7;18(3):573. doi: 10.3390/ijms18030573.

    PubMed 28272347
  • Rampazzo E, Del Bianco P, Bertorelle R, Boso C, Perin A, Spiro G, Bergamo F, Belluco C, Buonadonna A, Palazzari E, Lonardi S, De Paoli A, Pucciarelli S, De Rossi A. The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients. Br J Cancer. 2018 Mar 20;118(6):878-886. doi: 10.1038/bjc.2017.492. Epub 2018 Feb 15.

    PubMed 29449673
  • Augestad KM, Merok MA, Ignatovic D. Tailored Treatment of Colorectal Cancer: Surgical, Molecular, and Genetic Considerations. Clin Med Insights Oncol. 2017 Feb 16;11:1179554917690766. doi: 10.1177/1179554917690766. eCollection 2017.

    PubMed 28469509
  • Drebber U, Lay M, Wedemeyer I, Vallbohmer D, Bollschweiler E, Brabender J, Monig SP, Holscher AH, Dienes HP, Odenthal M. Altered levels of the onco-microRNA 21 and the tumor-supressor microRNAs 143 and 145 in advanced rectal cancer indicate successful neoadjuvant chemoradiotherapy. Int J Oncol. 2011 Aug;39(2):409-15. doi: 10.3892/ijo.2011.1036. Epub 2011 May 10.

    PubMed 21567082
  • Della Vittoria Scarpati G, Falcetta F, Carlomagno C, Ubezio P, Marchini S, De Stefano A, Singh VK, D'Incalci M, De Placido S, Pepe S. A specific miRNA signature correlates with complete pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):1113-9. doi: 10.1016/j.ijrobp.2011.09.030. Epub 2011 Dec 13.

    PubMed 22172905
  • Monsellato I, Garibaldi E, Cassinotti E, Baldari L, Boni L, Elmore U, Delpini R, Rosati R, Perinotti R, Alongi F, Bertocchi E, Gori S, Ruffo G, Pernazza G, Pulighe F, De Nisco C, Morpurgo E, Contardo T, Mammano E, Perna F, Menegatti B, Coratti A, Buccianti P, Balestri R, Ceccarelli C, Cavaliere D, Solaini L, Ercolani G, Traverso E, Fusco V, Torri V, Orecchia S. Expression levels of circulating miRNAs as biomarkers during multimodal treatment of rectal cancer - TiMiSNAR-mirna: a substudy of the TiMiSNAR Trial (NCT03962088). Trials. 2020 Jul 25;21(1):678. doi: 10.1186/s13063-020-04568-9.

    PubMed 32711544

Questions about this trial

What is this clinical trial studying?

An observational study of Rectal Cancer, run by Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 16 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Igor Monsellato, PhD (+390131206078, igor.monsellato@ospedale.al.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in expression levels of plasma miRNA (time frame: 5 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03962088, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Apr 2024.

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Timisnar - Biomarkers Substudy (Timisnar-mirna) | AzTrials