Response Assessment by Circulating Tumor DNA in Patients With Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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This is a single-arm observational study to determine the feasibility of assessing tumor response utilizing Circulating tumor DNA (ctDNA) in patients of with locally advanced rectal cancer (LARC) undergoing standard-of-care total neoadjuvant therapy (TNT) consisting of systemic chemotherapy (modified FOLFOX or modified FOLFIRINOX) followed by concurrent chemoradiation (50.4 Gy over approximately six weeks with concurrent radiosensitizing dose of capecitabine/5-fluorouracil).

Detailed Description
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In this observational study, patients with LARC who are selected for the standard-of-care TNT will be enrolled. After obtaining informed consent, a venous blood sample and the archival tissue block from the initial diagnostic rectal tumor biopsy will be sent to the Natera laboratory for designing patient-specific ctDNA assay, which will be used to measure ctDNA levels in the peripheral venous blood samples at various time points coinciding with the standard studies to assess tumor response. The blood sample needed for designing the assay and measuring the baseline ctDNA level will be obtained within four weeks before neoadjuvant chemotherapy begins. Subsequently, for patients undergoing 16 weeks of neoadjuvant chemotherapy, blood samples will be obtained for ctDNA level measurement at three time points ( after eight weeks/4 cycles of neoadjuvant chemotherapy within +/- 5 days of the magnetic resonance imaging (MRI) study, after 16 weeks/8 cycles of neoadjuvant chemotherapy within +/- 5 days of the MRI study, and one to 14 days before surgery ). For patients who receive eight weeks of neoadjuvant chemotherapy, two blood samples will be obtained for subsequent ctDNA measurements (after eight weeks/4 cycles of neoadjuvant chemotherapy within +/- 5 days of the MRI study, and one to 14 days before surgery). All patients may also choose to undergo additional serial ctDNA level measurements for surveillance after the surgery every three to four months for two years (optional). Tumor response rate assessed by ctDNA (defined as reduction of ctDNA level at least by 90% compared to the baseline level) will be compared with the response rate assessed by the standard method (proctoscopic examination, pelvic MRI, etc.) to explore if a significant correlation exists between these two response assessment methods. If preliminary data support the hypothesis that peripheral blood ctDNA can be utilized for tumor response assessment in this scenario, a larger study will be conducted to validate this method. Once validated, ctDNA measurement can potentially replace expensive, uncomfortable, and time-consuming methods of tumor response assessment like MRI.

Official Title
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A Prospective Observational Study to Determine the Feasibility of Tumor Response Assessment by Circulating Tumor DNA in Patients With Locally Advanced Rectal Cancer Undergoing Total Neoadjuvant Therapy

Conditions
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Rectal Cancer

Intervention / Treatment
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* Diagnostic Test: Circulating tumor DNA(ctDNA) level measurement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically or cytologically documented rectal cancer eligible for total neoadjuvant therapy (TNT). Male or female subjects ≥18 years old. Rectal tumor biopsy is available for SignateraTM assay development for ctDNA measurement. Patients must be able to understand the informed consent form and provide written consent. Exclusion Criteria: Patients without available rectal biopsy tissue for SignateraTM assay development. Patients with rectal cancer not eligible to receive standard-of-care TNT for any reason. Patients with undetectable ctDNA level in the baseline blood sample. Patients without trackable mutation in the rectal tumor.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Locally advanced rectal cancer patients<br>Patients with LARC undergoing TNT. | Diagnostic Test: Circulating tumor DNA(ctDNA) level measurement<br>* The ctDNA level will be measured using the Signatera platform developed by Natera, Inc. Signatera is a patient-specific, tumor informed custom-built ctDNA monitoring assay.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean serum ctDNA concentration | This measure is the concentration of ctDNA in plasma expressed as mean tumor molecules (MTM)/ml at specific time points. | Baseline, 8 weeks, 16 weeks, around 24 weeks before rectal surgery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response based on serum ctDNA level (change from baseline) | This measure is the number of subjects achieving a reduction of ctDNA level (mean tumor molecules[MTM]/ml) by > 90% compared to the baseline. | Baseline, 8 weeks, 16 weeks, around 24 weeks before rectal surgery | 
| Response based on standard clinical assessments | This measure is the number of subjects achieving a clinical change of tumor size based on standard clinical assessments. Response will be a determined as a subjective measure by experienced clinicians using any combination of pelvic MRI, visual proctoscopic examination, sigmoidoscopy, and/or endoscopic ultrasound. | Baseline, 8 weeks, 16 weeks, around 24 weeks before rectal surgery.] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally advanced rectal cancer