FAPI Molecular Imaging for Diagnosis of the CMS4 Unfavorable Colorectal Cancer Subtype

Sponsor
UMC Utrecht
Study ID
NCT06191120
Status
Recruiting
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Conditions

  • Metastatic Cancer to Liver
  • Metastatic Colorectal Cancer

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • [18F]-ALF-FAPI-74 PET/CT scan — RADIATION
    Participants will receive up to three \[18F\]-ALF-FAPI-74 PET/CT scans. \[18F\]-ALF-FAPI-74 is a PET tracer with high binding specificity and selectivity to FAP-expressing cells.

Study Details

Colorectal cancer (CRC) is the 3rd most common cancer worldwide and accounts for \~14,000 new diagnoses and \~5,000 deaths in the Netherlands yearly (1.9 million and 935 thousand on a global level). Large scale transcriptional profiling of primary CRC tumors has revealed the presence of four distinct consensus molecular subtypes (CMSs). The CMS4 subtype is associated with a poor prognosis, especially in early CRC, and may benefit less from several standard systemic treatments (e.g. oxaliplatin, 5-fluorouracil, cetuximab), while being relatively sensitive to irinotecan. This is relevant as in the metastatic setting often the first choice first-line systemic therapy regimen is oxaliplatin and not irinotecan-based. Furthermore, tumor cells can acquire a CMS4 phenotype following exposure to chemotherapy, which may contribute to therapy resistance. CMS4 accounts for \~25% of all early-stage CRC patients and is more prevalent in advanced disease stages (\~40% in stage IV CRC). Currently available CMS4 diagnostic tests require tumor tissue samples. The interpretation of biopsy-based CMS4 diagnosis is however complicated by large intra- and inter-lesion heterogeneity of CMS4 status. Extensive biopsy protocols could address the problem of CMS4 heterogeneity but are challenging in routine clinical practice. The development of CMS4-targeted therapy strategies therefore requires a more robust and clinically applicable diagnostic test for comprehensive quantitative assessment of CMS4 status of all lesions - primary and metastatic - in individual cancer patients. A promising solution for such a diagnostic test is to use a radiotracer that enables the quantitative assessment of CMS4 in vivo by whole body molecular imaging. This technique is particularly suited to assess biomarkers with heterogeneous expression: for diagnostic purposes, as a companion diagnostic for (targeted) therapies, or as part of a 'theranostic' strategy where patient selection using the diagnostic radiotracer is followed by treatment with the same tracer labeled to a therapeutic compound. Radiolabeled fibroblast activating protein inhibitor (FAPI) is an emerging diagnostic radiotracer that allows the comprehensive whole-body, whole-tumor assessment of fibroblast activation protein (FAP) expression in humans with a very low background uptake also at frequent CRC metastatic sites including the liver. FAP is an excellent candidate molecular imaging target for CMS4, as it is highly expressed on cancer-associated fibroblasts (CAF) that are abundantly present in this CRC subtype. Indeed, the investigators found that FAP gene-expression measured in tumor biopsies - as a single marker - accurately discriminates CMS4 from other CRC subtypes (area under the receiver operating characteristic curve (AUROC): 0.91; 95% confidence interval (CI): 0.90-0.93). The FoCus study will aim to take a next step by relating in vivo assessed FAP protein-expression by \[18F\]-ALF-FAPI-74 positron emission tomography (PET) / computed tomography (CT) to CMS4 status in patients eligible for colorectal liver metastatectomy as a first proof of concept. Ultimately this will contribute to the development of a diagnostic tool for the comprehensive assessment of CMS4 load in patients with (metastatic) CRC by using \[18F\]-ALF-FAPI-74 PET/CT molecular imaging, to guide CMS4 subtype-directed therapy decisions.

Key Dates

First listed
Jan 5, 2024
Start date
Aug 5, 2024
Status verified
May 2026
Primary completion
Sep 30, 2026
Completion
Jul 31, 2031

Study Design

Enrollment
45 participants (estimated)
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC

Arms

  • Experimental: One [18F]-ALF-FAPI-74 PET/CT scan
    For patients presenting with metachronous disease, or synchronous disease without the need for two separate surgical sessions for removal of all lesions (i.e. separate liver and primary cancer surgery), and who do not receive any chemotherapy before surgery, only one pre-surgical \[18F\]-ALF-FAPI-74 PET/CT will be performed.
  • Experimental: Two [18F]-ALF-FAPI-74 PET/CT scans
    For patients presenting with synchronous disease who require two separate surgical sessions (i.e. separate liver and primary cancer surgery), and who do not receive pre-surgical chemotherapy, an \[18F\]-ALF-FAPI-74 PET/CT will be performed before each surgical session.
  • Experimental: Pre-treated group, two [18F]-ALF-FAPI-74 PET/CT scans
    For patients presenting with metachronous disease, or synchronous disease without the need for two separate surgical sessions for removal of all lesions (i.e. separate liver and primary cancer surgery), and who receive pre-surgical chemotherapy, two \[18F\]-ALF-FAPI-74 PET/CTs are performed: one before chemotherapy and one before surgery.
  • Experimental: Pre-treated group, three [18F]-ALF-FAPI-74 PET/CT scans
    For patients presenting with synchronous disease who require two separate surgical sessions (i.e. separate liver and primary cancer surgery), and who do receive pre-surgical chemotherapy, three \[18F\]-ALF-FAPI-74 PET/CTs will be performed: one before chemotherapy and one before each surgical session.

Primary Outcome Measure

Tumor-level CMS4 status as assessed by the current RNA-sequencing based CMS4 status reference standard performed on fresh-frozen tissue samples following surgery. [ Time Frame: 1-10 months (dependent on standard-of-care) ]

Central Contacts

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