Early Detection of Treatment Failure in Metastatic Colorectal Cancer Patients

Study Overview
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Brief Summary
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In North America, colorectal cancer patients with resectable liver-restricted metastases (mCRC-LR) are treated with approximately 6 months of preoperative systemic multi-agent chemotherapy. Actuarial data however supports that approximately 20% of mCRC-LR patients can be cured without as much systemic chemotherapy. Prospective phase II-III trials also support that awaiting recurrence to initiate further metastases-targeted or systemic treatment may provide patients with longer overall survival while avoiding toxicities in those without recurrence.

Detailed Description
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The general objective of this single-centre, prospective observational cohort study in 100 mCRC-LR patients treated with curative intent along standard of care (SOC), is to obtain real-world data on administered therapies, selected complications, and oncological outcomes, while longitudinally collecting biospecimens to enable correlative research investigating early biological markers of treatment resistance and recurrence. Cryopreservation of sequential blood derivatives, tumor tissue, and stool samples will allow investigation of circulating tumor DNA (ctDNA), T-cell receptor repertoire, somatic cancer mutations, immune and other gene expression, gut microbiome, and soluble factors. The first biological marker that will be investigated in correlative research will be longitudinal measurements of ctDNA targeting 30 oncogenes, 23 axons, and 146 hotspots (Follow It assay, Canexia Health). Additional biological markers will be defined in subsequent amendments to this protocol. The results are expected to provide important insights for the design of future trials investigating ways to personalize therapy, such as to: a) avoid the unnecessary use of neoadjuvant or adjuvant systemic chemotherapy, b) avoid morbid hepatectomies in patients unlikely to benefit, c) test novel preoperative therapies in patients more likely to benefit, and d) modulate the intensity of follow-up.

Official Title
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A Prospective Observational Cohort Study for Early Detection of Treatment Failure in Metastatic Colorectal Cancer Patients Undergoing Systemic Chemotherapy and Liver Resection With Curative Intent

Conditions
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Colorectal Cancer Metastatic

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients (≥18 years of age at the time of consent); Stage IV colon or rectal adenocarcinoma with liver-restricted metastasis(es) for whom partial hepatectomy with curative intent is planned; Instead of, or in addition to, partial hepatectomy, liver metastases may be ablated by needle radio frequency or microwave; in case of a solitary liver metastasis, three core-needle biopsies are provided for research at time of the procedure and prior to tissue destruction; Patients may undergo planned two-stage partial hepatectomies; Patients may have at baseline lung micro nodules or intra-abdominal enlarged nodes or nodules of unknown nature, not considered as extra-hepatic metastases in the opinion of the investigator; Patients who are scheduled to receive FOLFOX-based pre-hepatectomy may receive any additional combined agents, such as and not limited to Irinotecan, anti-EGFR, and anti-VEGF drugs; Patients are willing and able to provide serial blood samples, tumor and adjacent tissues, and stool samples for research; The timing and specific treatments of the primary colon or rectal tumor is per SOC, at the discretion of the treating physician, including the use of pre-operative radiotherapy for rectal cancer; Patients may receive post-operative adjuvant chemotherapy per SOC, at the discretion of the treating physician; Patients must consent to the Exactis Personalized my Treatment registry. Exclusion Criteria: Pregnant or breastfeeding patients, Hereditary colorectal cancer (e.g., familial colonic polyposis or Lynch syndrome), and Presence of concurrent other cancer(s).

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 |
| --- | --- |
| Observational<br>We plan to recruit up to 100 mCRC patients with baseline resectable liver-restricted metastases (mCRC-LR) without evidence of extra-hepatic metastases, with primary tumor already or to be resected (metachronous or synchronous disease), planned to receive upfront FOLFOX-based preoperative neoadjuvant systemic chemotherapy, who achieved no-evidence of disease (NED) in the abdomen by standard imaging. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiological response to pre-operative chemotherapy as assessed by RECIST v1.1 |  | Approximately three months | 
| Biochemical response to pre-operative chemotherapy as assessed by plasmatic CEA measurement, change from baseline after 4 cycles of chemotherapy |  | Approximately three months | 
| Pathological response to pre-operative chemotherapy as assessed by Ryan and Rubbia Brandt Tumor Regression Grade (TRG) scores on resected tumors |  | Approximately three months | 
| Tumor response to pre-operative chemotherapy as assessed by change in circulating tumor DNA level, change from baseline | Follow It assay, Canexia Health | Approximately three months | 
| Histopathologic growth pattern as assessed by percent replacement, desmoplastic, and pushing features measured at the interface of liver metastasis and non tumoral liver |  | Three to four months | 
| Post-operative minimal residual disease as assessed by circulating tumor DNA detection after tumor resection with curative intent | Follow It assay, Canexia Health | Approximately 1 months after resection with curative intent | 
| Time to radiological recurrence after tumor resection with curative intent |  | Up to three years after tumor resection with curative intent | 
| Time to biochemical recurrence as assessed by plasmatic CEA measurement, level above the upper limit occurring after tumor resection with curative intent |  | Up to three years after tumor resection with curative intent | 
| Time to tumor recurrence as assessed by detection or change in level of circulating tumor DNA after tumor resection with curative intent | Follow It assay, Canexia Health | Up to three years after tumor resection with curative intent | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and grade of FOLFOX-induced neuropathy, as assessed by Sensory Subscale of the NCI CTCAE scale, version 3 |  | Two to three months pre-operatively and during post-operative adjuvant chemotherapy | 
| Incidence of allergic reaction to oxaliplatin diagnosed by treating physicians and requiring desensitization or change in chemotherapy regimen |  | Two to three months pre-operatively and during post-operative adjuvant chemotherapy | 
| Incidence of hospitalization for febrile neutropenia diagnosed by treating physicians |  | Two to three months pre-operatively and during post-operative adjuvant chemotherapy | 
| Ninety-day post-surgical complications, defined by Clavien Dindo grading system |  | 90 days after tumor resection | 
| Disease-specific survival after complete tumor resection |  | Up to three years after tumor resection with curative intent | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Real world data, Observational study, Circulating tumor DNA, Microbiome, Tumor immunology, Metastatic colorectal cancer, Liver metastasis, Biomarker