GUIDE.MRD-01-CRC: Clinical Validation and Benchmarking of Top Performing ctDNA Diagnostics - Colorectal Cancer

GUIding Multi-moDal thErapies Against MRD by Liquid Biopsies in Colorectal Cancer - GUIDE.MRD-01-CRC

Improving personalized cancer treatments and finding the best strategies to treat each patient relies on using new diagnostic technologies. Currently, for colorectal cancer, the methods used to decide who gets additional post-surgery treatment are suboptimal. Some patients get too much treatment, while others do not get enough.

There is a new way to explore if there is any cancer left in a patient's body using circulating tumor DNA (ctDNA) detected in blood samples. This can help decide who needs more treatment after surgery. Even though many tests have been developed, it has yet to be determined which test performs best at relevant time points.

The GUIDE.MRD consortium is a group of experts, including scientists, technology, and pharmaceutical companies. The consortium is working on creating a reliable standard for the ctDNA tests, validating their clinical utility, and collecting data to help decide on the best treatment for each patient.

GUIDE.MRD-01-CRC is a part of the GUIDE.MRD project.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer Stage III; Liver Metastasis Colon Cancer

Detailed Description

GUIDE.MRD-01-CRC is a part of WP3 of the overarching GUIDE.MRD project. Each study chair has a local clinical trial protocol where patients are recruited. After the end of recruitment, samples will be analyzed under the GUIDE.MRD consortium.

The overall aim of GUIDE.MRD is to investigate the clinical utility of ctDNA analysis to predict and guide the choice of multi-modal therapies prospectively. The fundamental steps towards this aim are assessment and benchmarking of the many available ctDNA diagnostics to identify the best-suited tests for clinical application. Clinical samples will be used to benchmark ctDNA diagnostics and assess their true clinical performance. The samples should reflect clinical situations where the ctDNA diagnostics are particularly useful, such as post-operatively, post-adjuvant, during chemotherapy, and longitudinally during post-treatment surveillance. In these situations, ctDNA diagnostics could be used to either monitor treatment response (in case of MRD after surgery) or to identify relapse at an early time point. Based on ctDNA information, medical treatment could be changed, or radiology could be used to reveal the location of residual disease.

The rationale for the observational clinical study GUIDE.MRD-01-CRC is to prospectively collect the clinical samples needed to enable assessment of the performance of ctDNA diagnostics in the setting of colorectal cancer (CRC). There are two main scenarios where ctDNA diagnostic is useful in CRC:

Stage III CRC (locally advanced, non-metastasized disease): This patient group is particularly relevant because adjuvant therapy is recommended for all stage III patients, due to their high recurrence risk, ~25%. Nevertheless, most patients do not recur, and most of these do not need therapy at all, because they were already cured by surgery alone, which leads to substantial overtreatment. Furthermore, the 25% of patients who recur despite both surgery and adjuvant therapy, probably could benefit from further multimodal therapies. The challenge is, however, that currently there is no marker in clinical use that can identify those patients with residual disease and need for therapy. Circulating tumor DNA is potentially such a marker. However, currently, it is unknown, which, if any, of the many different ctDNA diagnostics developed in recent years have the required performance to provide clinical utility in the management of stage III CRC. This clinical dilemma will be addressed with the first cohort of GUIDE.MRD-01-CRC.

Metastatic CRC with isolated liver metastases. Metastatic CRC with liver metastases is a unique tumor type in that surgical resection or complete ablation of the metastases, is the standard of care. In virtually all other tumor types, resection of liver metastases is considered only within clinical trials or in exceptional clinical circumstances. In contrast, resection, or ablation of colorectal cancer liver metastases (CRLM) are routinely performed with curative intention, and the overall 5-year survival is around 50%. Most relapses present within three years after operative intervention. The clinical benefit of adjuvant chemotherapy is currently a matter of debate, due to limited data from randomized controlled trials and recent results that indicate inferior overall survival (OS) in patients who received adjuvant therapy (JCOG0603). Based on these and earlier data (EORTC Trial 40983) that failed to show an OS benefit of adjuvant therapy after CRLM resection, it can be assumed that most patients are treated unnecessarily with chemotherapy, and those patients that could receive targeted agents are missed. No histological or clinical markers are available to guide decisions on adjuvant treatment. In this setting, ctDNA could be valuable to guide decisions on adjuvant chemotherapy (yes/no), the addition of biologicals such as anti-VEGF and anti-EGFR agents, targeted therapies in the case of BRAF mutations, or the presence of microsatellite instability (MSI), for example.

Primary objectives:

• To assess the performance of ctDNA diagnostics using samples collected at the two-landmark time-points "post-surgery" and "post-adjuvant therapy". Sensitivity, specificity, and positive and negative predictive values of the ctDNA diagnostics will be determined to enable a head-to-head performance assessment and benchmarking of ctDNA diagnostics

Secondary objectives

• To assess the ctDNA stratified 3-year recurrence-free survival (RFS)
• To assess the lead time between ctDNA detection and clinical recurrence
• To assess the capacity of the ctDNA diagnostics to predict response to adjuvant therapy

• Study Type: Observational
• Enrollment (Estimated): 590

Contacts and Locations

• Study Contact: Name: Claus L Andersen, PhD; Phone Number: +45 7845 5319; Email: cla@clin.au.dk
• Study Contact Backup: Name: Mads H Rasmussen, PhD; Phone Number: +45 7845 5314; Email: mads.heilskov@clin.au.dk

Study Locations

• Austria
  • Styria
    • Graz, Styria, Austria, 8010
      • Recruiting
      • Abteilung für Onkologie, Medizinische Universität Graz
      • Contact: Armin Gerger, MD, PhD; Phone Number: +43-316-385-80625; Email: armin.gerger@medunigraz.at
    • Graz, Styria, Austria, 8010
      • Recruiting
      • Ordenskrankenhaus Graz Mitte
      • Contact: Felix Aigner, MD, PhD; Phone Number: +43-316-7067-13002; Email: Felix.Aigner@bbgraz.at
• Denmark
  • Capital Region of Denmark
    • Copenhagen, Capital Region of Denmark, Denmark, 2400
      • Recruiting
      • Bispebjerg Hospital
      • Contact: Nis Hallundbæk Schlesinger; Email: Nis.Hallundbaek.Schlesinger@regionh.dk
    • Herlev, Capital Region of Denmark, Denmark, 2730
      • Not yet recruiting
      • Herlev Hospital
      • Contact: Mads F Klein, MD, Ph.D; Email: mads.falk.klein@regionh.dk
      • Contact: Jeppe Kildsig, MD; Email: Jeppe.Kildsig@regionh.dk
  • Central Jutland
    • Aarhus, Central Jutland, Denmark, 8000
      • Recruiting
      • Aarhus University Hospital
      • Contact: Lene H Iversen, MD, DMSc; Email: lene.h.iversen@dadlnet.dk
    • Herning, Central Jutland, Denmark, 7400
      • Recruiting
      • Gødstrup Hospital
      • Contact: Claudia Jaensch, MD, PhD; Email: Claudia.Jaensch@goedstrup.rm.dk
    • Horsens, Central Jutland, Denmark, 8700
      • Recruiting
      • Regional Hospital Horsens
      • Contact: Kåre A Gotschalck, MD, Ph.D; Email: kaarsune@rm.dk
    • Randers, Central Jutland, Denmark, 8930
      • Recruiting
      • Regional Hospital Randers
      • Contact: Peter Bondeven, MD, PhD; Email: petefred@rm.dk
    • Viborg, Central Jutland, Denmark, 8800
      • Recruiting
      • Regional Hospital Viborg
      • Contact: Uffe S Løve, MD, PhD; Email: uffescho@rm.dk
  • North Denmark
    • Aalborg, North Denmark, Denmark, 9000
      • Recruiting
      • Aalborg University Hospital
      • Contact: Ole Thorlacius-Ussing, MD, PhD; Email: otu@rn.dk
  • The Region of Southern Denmark
    • Odense, The Region of Southern Denmark, Denmark, 5000
      • Recruiting
      • Odense University Hospital
      • Contact: Per Vadgaard Andersen, MD, PhD; Email: Per.vadgaard.andersen@rsyd.dk
• France
  • Montpellier, France, 34295
    • Recruiting
    • LCCRH (Laboratoire Cellules Circulantes Rares Humaines) - CHU de Montpellier
    • Contact: Catherine Alix-Panabiéres, PhD; Phone Number: +33 (0)4 11 75 99 31; Email: c-panabieres@chu-montpellier.fr
    • Contact: Thomas Bardol, MD; Phone Number: +33 (0)4 11 75 99 31; Email: t-bardol@chu-montpellier.fr
• Germany
  • Free and Hanseatic City of Hamburg
    • Hamburg, Free and Hanseatic City of Hamburg, Germany, 20246
      • Recruiting
      • Universitatsklinikum Hamburg-Eppendorf
      • Contact: Daniel J Smit, MD, PhD; Phone Number: +49 (0) 40 7410 - 57495; Email: d.smit@uke.de
    • Hamburg, Free and Hanseatic City of Hamburg, Germany, 20246
      • Recruiting
      • Department of General-, Visceral- and Thoracic Surgery, University Medical Center Hamburg-Eppendorf
      • Contact: Thilo Hackert, MD, MBA; Phone Number: +49 (0) 40 7410 - 52401; Email: allgemeinchirurgie@uke.de
      • Contact: Nathaniel Melling, MD; Phone Number: +49 (0) 40 7410 - 50162; Email: n.melling@uke.de
• Sweden
  • Stockholm County
    • Huddinge, Stockholm County, Sweden, 14183
      • Recruiting
      • Karolinska University Hospital
      • Contact: Marco Gerling, MD; Phone Number: 0468-123 800 00; Email: marco.gerling@ki.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Colorectal cancer stage III: patient with stage III colorectal cancer treated with curative-intent surgery and adjuvant chemotherapy

Colorectal cancer liver metastasis: patient with colorectal cancer liver metastasis

Description

Colorectal cancer stage III

Inclusion Criteria:

• Colorectal cancer, UICC stage III
• Has received curative-intent resection and is a candidate for adjuvant chemotherapy
• Patient able to understand and sign written informed consent

Exclusion Criteria:

• Hereditary colorectal cancer linked to familial colonic polyposis or Lynch syndrome
• Inflammatory bowel disease (Crohn's disease or ulcerative colitis)
• Verified distant metastases
• Not treated with adjuvant chemotherapy despite indication (incomplete treatment not included)
• Treated with neoadjuvant chemo-radiation therapy
• No tissue sample available for the project, or tumor content in the tissue sample is <20%
• Synchronous colorectal and non-colorectal cancer diagnosed per operative (except skin cancer other than melanoma)
• Other cancers (excluding colorectal cancer or skin cancer other than melanoma) within 3 years from eligibility screening
• Patients who are unlikely to comply with the protocol (e.g. uncooperative attitude), inability to return for subsequent visits) and/or otherwise considered by the Investigator to be unlikely to complete the study

Colorectal cancer liver metastasis

Inclusion Criteria:

• Colorectal cancer liver metastasis
• Planned for curative-intent treatment
• Performance status 0-1

Exclusion Criteria:

• Liver cirrhosis
• Extrahepatic metastases
• Other cancer within the last 5 years
• Intervention not performed with curative intent
• No tissue available from CRLM or primary tumor

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Colorectal cancer stage III
Colorectal cancer liver metastasis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Collection of clinical plasma samples at relevant time points	For head-to-head performance assessment and benchmarking of ctDNA diagnostics	8 months after end of recruitment

Secondary Outcome Measures

Outcome Measure	Time Frame
The 3-year recurrence-free survival	3 years after end of recruitment
Lead time between ctDNA detection and clinical recurrence	3 years after end of recruitment
Prognostic value of ctDNA analysis at relevant time points	3 years after end of recruitment

Collaborators and Investigators

• Sponsor: Claus Lindbjerg Andersen
• Collaborators: Karolinska Institutet; Medical University of Graz; University of Aarhus; Universitätsklinikum Hamburg-Eppendorf; University Medical Centre of Montpellier
• Investigators: Study Chair: Ellen Heitzer, PhD, Medical University of Graz; Study Chair: Klaus Pantel, MD, Universitatsklinikum Hamburg-Eppendorf; Study Chair: Catherine Alix-Panabiéres, PhD, University Medical Centre of Montpellier; Study Chair: Matthias Löhr, MD, Karolinska Institutet; Study Director: Claus L Andersen, PhD, Aarhus University Hospital

Publications and helpful links

Helpful Links

• Webpage of the GUIDE.MRD project

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): July 31, 2031

Study Registration Dates

• First Submitted: October 26, 2023
• First Submitted That Met QC Criteria: October 26, 2023
• First Posted (Actual): November 1, 2023

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Circulating tumor DNA; Minimal residual disease; ctDNA diagnostics
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Colorectal Neoplasms; Neoplasm, Residual
• Other Study ID Numbers: GUIDE.MRD-01-CRC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No