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Timisnar - Biomarkers Substudy (Timisnar-mirna) (TiMiSNAR-miRNA)
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 |
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:
- Taking blood samples is less invasive, less expensive, easy to schedule, and nearly without any severe complications.
- 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
- 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.
- 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.
| 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 SubStudy |
| Actual Study Start Date : | April 1, 2019 |
| Estimated Primary Completion Date : | April 1, 2023 |
| Estimated Study Completion Date : | April 1, 2023 |
- 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
- miRNA expression and surgery [ Time Frame: 5 years ]changes in expression levels of miRNA following complete surgical resection with disease-free survival
- miRNA expression and surveillance [ Time Frame: 5 years ]the relation between changes in miRNA during surveillance and tumor relapse
Biospecimen Retention: Samples Without DNA
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date | May 21, 2019 | ||||
| First Posted Date | May 23, 2019 | ||||
| Last Update Posted Date | February 18, 2020 | ||||
| Actual Study Start Date | April 1, 2019 | ||||
| Estimated Primary Completion Date | April 1, 2023 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures |
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
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| Original Primary Outcome Measures | Same as current | ||||
| Change History | |||||
| Current Secondary Outcome Measures |
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| Original Secondary Outcome Measures | Same as current | ||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||
| Descriptive Information | |||||
| Brief Title | Timisnar - Biomarkers Substudy (Timisnar-mirna) | ||||
| Official Title | Timing To Minimally Invasive Surgery After Neoadjuvant Chemoradiotherapy For Rectal Cancer: A Multicenter Randomized Controlled Trial - Biomarkers SubStudy | ||||
| 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. |
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| 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:
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 | ||||
| Study Design | Observational Model: Cohort Time Perspective: Prospective |
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| Target Follow-Up Duration | Not Provided | ||||
| Biospecimen | Retention: Samples Without DNA Description:
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.
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| 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. | ||||
| Condition | Rectal Cancer | ||||
| Intervention | 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. |
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| Study Groups/Cohorts | Not Provided | ||||
| Publications * |
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||
| Recruitment Status | Recruiting | ||||
| Estimated Enrollment |
200 | ||||
| Original Estimated Enrollment | Same as current | ||||
| Estimated Study Completion Date | April 1, 2023 | ||||
| Estimated Primary Completion Date | April 1, 2023 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria |
Inclusion Criteria:
Exclusion Criteria:
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| Sex/Gender |
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| Ages | 18 Years and older (Adult, Older Adult) | ||||
| Accepts Healthy Volunteers | No | ||||
| Contacts |
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| Listed Location Countries | Italy | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number | NCT03962088 | ||||
| Other Study ID Numbers | A19 | ||||
| Has Data Monitoring Committee | Yes | ||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement |
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| Responsible Party | Igor Monsellato, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria | ||||
| Study Sponsor | Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria | ||||
| Collaborators | Not Provided | ||||
| Investigators | Not Provided | ||||
| PRS Account | Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria | ||||
| Verification Date | February 2020 | ||||
