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

NCT06191120 | Recruiting

• 2 other identifiers: U23-06072023-509183-17
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Colorectal Cancer; Metastatic Cancer to Liver

Keywords

CMS4; FAPI; Imaging

Outcome Measures

Primary Outcomes (1)

• Tumor-level CMS4 status as assessed by the current RNA-sequencing based CMS4 status reference standard performed on fresh-frozen tissue samples following surgery.

  To assess the discriminative ability of pre-surgical in vivo \[18F\]-ALF-FAPI-74 uptake for CMS4 CRC on a tumor lesion-level in patients eligible for colorectal liver meta-statectomy

  1-10 months (dependent on standard-of-care)

Secondary Outcomes (5)

• FAP protein expression per lesion measured by Enzyme-linked Immunosorbent Assay (ELISA) and immunohistochemistry (IHC)

  1-10 months (dependent on standard-of-care)

• The occurrence, type, and severity of (serious) adverse events (none expected)

  1-10 months (dependent on standard-of-care)

• [18F]-ALF-FAPI-74 standardized uptake values in reference liver and blood pool according to different body-composition correction formulas

  1-10 months (dependent on standard-of-care)

• Change in the [18F]-ALF-FAPI-74 standardized uptake values per lesion during chemotherapy

  1-10 months (dependent on standard-of-care)

• 10-120 minutes post-injection dynamic [18F]-ALF-FAPI-74 uptake levels in tumor lesions and reference organs

  1-10 months (dependent on standard-of-care)

Other Outcomes (9)

• [18F]-ALF-FAPI-74 standardized uptake values measured in volumes of interest (VOIs) within targeted and non-targeted tissues

  1-10 months (dependent on standard-of-care)

• Site-specific recurrence free survival

  5 years

• Overall survival

  5 years

Study Arms (4)

One [18F]-ALF-FAPI-74 PET/CT scan

EXPERIMENTAL

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.

Radiation: [18F]-ALF-FAPI-74 PET/CT scan

Two [18F]-ALF-FAPI-74 PET/CT scans

EXPERIMENTAL

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.

Radiation: [18F]-ALF-FAPI-74 PET/CT scan

Pre-treated group, two [18F]-ALF-FAPI-74 PET/CT scans

EXPERIMENTAL

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.

Radiation: [18F]-ALF-FAPI-74 PET/CT scan

Pre-treated group, three [18F]-ALF-FAPI-74 PET/CT scans

EXPERIMENTAL

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.

Radiation: [18F]-ALF-FAPI-74 PET/CT scan

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.

One [18F]-ALF-FAPI-74 PET/CT scan; Pre-treated group, three [18F]-ALF-FAPI-74 PET/CT scans; Pre-treated group, two [18F]-ALF-FAPI-74 PET/CT scans; Two [18F]-ALF-FAPI-74 PET/CT scans

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years.
• Candidates for liver metastatectomy at the time of liver metastasis diagnosis as clinically indicated in the tumor board (RAKU).
• Patients must have given written informed consent.
• At least one liver metastasis should have a longest diameter of a least 1.5 cm as measured on routinely performed imaging (e.g. magnetic resonance imaging, CT-scan or ultrasound). This minimum diameter will guarantee sufficient tissue material for analysis and will prevent underestimation of \[18F\]-ALF-FAPI-74 uptake due to partial volume effects.
• CRC patients who received prior treatment before clinical indication for surgical liver metastases resection (both synchronous and metachronous patients, as well as a re-resection of liver metastatic disease) are allowed to enter the study. This is because our prime interest is in the relation between FAPI uptake and the presence of CMS4 at the same point in time, which will likely not be biased by earlier therapies.
• It is allowed for patients to receive concurrent radiofrequency ablation or other local treatments directed to other metastatic disease locations, if at least one liver metastasis of sufficient size is planned to be surgically removed and therefore available for tissue analysis.
• It is allowed for patients to be treated with pre-surgical radiotherapy directed to the primary tumor (e.g. in rectal cancer patients).

You may not qualify if:

• Pregnancy.
• Patients treated with a pre-surgical chemotherapy regimen that does not include a fluoropyrimidine.

Sponsors & Collaborators

• UMC Utrecht: lead

Study Sites (1)

University Medical Center Utrecht

Utrecht, Utrecht, 3584 CX, Netherlands

RECRUITING

Related Publications (12)

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  PMID: 26457759 BACKGROUND

• Trumpi K, Ubink I, Trinh A, Djafarihamedani M, Jongen JM, Govaert KM, Elias SG, van Hooff SR, Medema JP, Lacle MM, Vermeulen L, Borel Rinkes IHM, Kranenburg O. Neoadjuvant chemotherapy affects molecular classification of colorectal tumors. Oncogenesis. 2017 Jul 10;6(7):e357. doi: 10.1038/oncsis.2017.48.

  PMID: 28692036 BACKGROUND

• Peters NA, Constantinides A, Ubink I, van Kuik J, Bloemendal HJ, van Dodewaard JM, Brink MA, Schwartz TP, Lolkema MPJK, Lacle MM, Moons LM, Geesing J, van Grevenstein WMU, Roodhart JML, Koopman M, Elias SG, Borel Rinkes IHM, Kranenburg O. Consensus molecular subtype 4 (CMS4)-targeted therapy in primary colon cancer: A proof-of-concept study. Front Oncol. 2022 Sep 6;12:969855. doi: 10.3389/fonc.2022.969855. eCollection 2022.

  PMID: 36147916 BACKGROUND

• Lindner T, Loktev A, Altmann A, Giesel F, Kratochwil C, Debus J, Jager D, Mier W, Haberkorn U. Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein. J Nucl Med. 2018 Sep;59(9):1415-1422. doi: 10.2967/jnumed.118.210443. Epub 2018 Apr 6.

  PMID: 29626119 BACKGROUND

• Loktev A, Lindner T, Mier W, Debus J, Altmann A, Jager D, Giesel F, Kratochwil C, Barthe P, Roumestand C, Haberkorn U. A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts. J Nucl Med. 2018 Sep;59(9):1423-1429. doi: 10.2967/jnumed.118.210435. Epub 2018 Apr 6.

  PMID: 29626120 BACKGROUND

• Giesel FL, Adeberg S, Syed M, Lindner T, Jimenez-Franco LD, Mavriopoulou E, Staudinger F, Tonndorf-Martini E, Regnery S, Rieken S, El Shafie R, Rohrich M, Flechsig P, Kluge A, Altmann A, Debus J, Haberkorn U, Kratochwil C. FAPI-74 PET/CT Using Either 18F-AlF or Cold-Kit 68Ga Labeling: Biodistribution, Radiation Dosimetry, and Tumor Delineation in Lung Cancer Patients. J Nucl Med. 2021 Feb;62(2):201-207. doi: 10.2967/jnumed.120.245084. Epub 2020 Jun 26.

  PMID: 32591493 BACKGROUND

• Lindner T, Altmann A, Giesel F, Kratochwil C, Kleist C, Kramer S, Mier W, Cardinale J, Kauczor HU, Jager D, Debus J, Haberkorn U. 18F-labeled tracers targeting fibroblast activation protein. EJNMMI Radiopharm Chem. 2021 Aug 21;6(1):26. doi: 10.1186/s41181-021-00144-x.

  PMID: 34417894 BACKGROUND

• Ubink I, Elias SG, Moelans CB, Lacle MM, van Grevenstein WMU, van Diest PJ, Borel Rinkes IHM, Kranenburg O. A Novel Diagnostic Tool for Selecting Patients With Mesenchymal-Type Colon Cancer Reveals Intratumor Subtype Heterogeneity. J Natl Cancer Inst. 2017 Aug 1;109(8). doi: 10.1093/jnci/djw303.

  PMID: 28376187 BACKGROUND

• Strating E, Wassenaar E, Verhagen M, Rauwerdink P, van Schelven S, de Hingh I, Rinkes IB, Boerma D, Witkamp A, Lacle M, Fodde R, Volckmann R, Koster J, Stedingk K, Giesel F, de Roos R, Poot A, Bol G, Lam M, Elias S, Kranenburg O. Fibroblast activation protein identifies Consensus Molecular Subtype 4 in colorectal cancer and allows its detection by 68Ga-FAPI-PET imaging. Br J Cancer. 2022 Jul;127(1):145-155. doi: 10.1038/s41416-022-01748-z. Epub 2022 Mar 16.

  PMID: 35296803 BACKGROUND

• Mori Y, Haberkorn U, Giesel FL. 68Ga- or 18F-FAPI PET/CT-what it can and cannot. Eur Radiol. 2023 Nov;33(11):7877-7878. doi: 10.1007/s00330-023-09715-9. Epub 2023 May 12. No abstract available.

  PMID: 37171487 BACKGROUND

• Watabe T, Naka S, Tatsumi M, Kamiya T, Kimura T, Shintani Y, Abe K, Miyake T, Shimazu K, Kobayashi S, Kurokawa Y, Eguchi H, Doki Y, Inohara H, Kato H, Mori Y, Cardinale J, Giesel FL. Initial Evaluation of [18F]FAPI-74 PET for Various Histopathologically Confirmed Cancers and Benign Lesions. J Nucl Med. 2023 Aug;64(8):1225-1231. doi: 10.2967/jnumed.123.265486. Epub 2023 Jun 2.

  PMID: 37268427 BACKGROUND

• Loktev A, Lindner T, Burger EM, Altmann A, Giesel F, Kratochwil C, Debus J, Marme F, Jager D, Mier W, Haberkorn U. Development of Fibroblast Activation Protein-Targeted Radiotracers with Improved Tumor Retention. J Nucl Med. 2019 Oct;60(10):1421-1429. doi: 10.2967/jnumed.118.224469. Epub 2019 Mar 8.

  PMID: 30850501 BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• M. G.E.H. Lam

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

Central Study Contacts

M. van Duijvenvoorde

CONTACT

+31 088 75 56474; m.vanduijvenvoorde@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: FoCus is a prospective monocenter, proof-of-concept, observational clinical study with a cross-sectional design to address the primary objective, and a longitudinal part to address secondary and exploratory objectives. Participant will receive up to three \[18\]F-ALF-FAPI-74 PET/CT scans, dependent on standard-of-care procedures.

Study Record Dates

• First Submitted: December 19, 2023
• First Posted: January 5, 2024
• Study Start: August 5, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): July 1, 2031
• Last Updated: May 14, 2026

Record last verified: 2026-05

Locations

NL (1)