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Research ArticleClinical Investigation

First-in-Humans PET Imaging of Tissue Factor in Patients with Primary and Metastatic Cancers Using 18F-labeled Active-Site Inhibited Factor VII (18F-ASIS): Potential as Companion Diagnostic

Mathias Loft, Camilla Christensen, Malene M. Clausen, Esben A. Carlsen, Carsten P. Hansen, Niels Kroman, Seppo W. Langer, Claus Høgdall, Jacob Madsen, Nic Gillings, Carsten H. Nielsen, Thomas L. Klausen, Søren Holm, Annika Loft, Anne K. Berthelsen and Andreas Kjaer
Journal of Nuclear Medicine December 2022, 63 (12) 1871-1879; DOI: https://doi.org/10.2967/jnumed.122.264068
Mathias Loft
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
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Camilla Christensen
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
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Malene M. Clausen
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
2Department of Oncology, Copenhagen University Hospital – Rigshospitalet, Denmark;
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Esben A. Carlsen
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
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Carsten P. Hansen
3Department of Surgery, Copenhagen University Hospital – Rigshospitalet, Denmark;
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Niels Kroman
4Department of Breast Surgery, Copenhagen University Hospital – Rigshospitalet, Denmark;
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Seppo W. Langer
2Department of Oncology, Copenhagen University Hospital – Rigshospitalet, Denmark;
5Department of Clinical Medicine, University of Copenhagen, Denmark;
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Claus Høgdall
6Department of Gynecology, Copenhagen University Hospital – Rigshospitalet, Denmark and
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Jacob Madsen
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
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Nic Gillings
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
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Carsten H. Nielsen
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
7Minerva Imaging ApS, Denmark
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Thomas L. Klausen
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
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Søren Holm
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
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Annika Loft
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
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Anne K. Berthelsen
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
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Andreas Kjaer
1Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital – Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, Denmark;
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Abstract

Tissue factor (TF) expression in cancers correlates with poor prognosis. Recently, the first TF-targeted therapy was approved by the U.S. Food and Drug Administration for cervical cancer. To unfold the potential of TF-targeted therapies, correct stratification and selection of patients eligible for treatments may become important for optimization of patient outcomes. TF-targeted PET imaging based on 18F-radiolabeled active-site inhibited versions of the TF natural ligand coagulation factor VII (18F-ASIS) has in preclinical models convincingly demonstrated its use for noninvasive quantitative measurements of TF expression in tumor tissue. 18F-ASIS PET imaging thus has the potential to act as a diagnostic companion for TF-targeted therapies in the clinical setting. Methods: In this first-in-humans trial, we included 10 cancer patients (4 pancreatic, 3 breast, 2 lung, and 1 cervical cancer) for 18F-ASIS PET imaging. The mean and SD of administered 18F-ASIS activity was 157 ± 35 MBq (range, 93–198 MBq). PET/CT was performed after 1, 2, and 4 h. The primary objectives were to establish the safety, biodistribution, pharmacokinetics, and dosimetry of 18F-ASIS. Secondary objectives included quantitative measurements of SUVs in tumor tissue with PET and evaluation of the correlation (Pearson correlation) between tumor SUVmax and ex vivo TF expression in tumor tissue. Results: Administration of 18F-ASIS was safe, and no adverse events were observed. No clinically significant changes in vital signs, electrocardiograms, or blood parameters were observed after injection of 18F-ASIS. Mean 18F-ASIS plasma half-life was 3.2 ± 0.6 h, and the radiotracer was predominantly excreted in the urine. For injection activity of 200 MBq of 18F-ASIS, effective whole-body dose was 4 mSv and no prohibitive organ-specific absorbed doses were found. Heterogeneous radiotracer uptake was observed across patients and within tumors. We found a trend of a positive correlation between tumor SUVmax and ex vivo TF expression (r = 0.84, P = 0.08, n = 5). Conclusion: 18F-ASIS can be safely administered to cancer patients for PET imaging of TF expression in tumors. The trial marks the first test of a TF-targeted PET radiotracer in humans (first-in-class). The findings represent important first steps toward clinical implementation of 18F-ASIS PET imaging of TF expression.

  • active site inhibited factor VII (ASIS)
  • tissue factor
  • PET/CT
  • first-in-humans
  • phase I clinical trial

Footnotes

  • Published online May. 19, 2022.

  • © 2022 by the Society of Nuclear Medicine and Molecular Imaging.
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Journal of Nuclear Medicine: 63 (12)
Journal of Nuclear Medicine
Vol. 63, Issue 12
December 1, 2022
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First-in-Humans PET Imaging of Tissue Factor in Patients with Primary and Metastatic Cancers Using 18F-labeled Active-Site Inhibited Factor VII (18F-ASIS): Potential as Companion Diagnostic
Mathias Loft, Camilla Christensen, Malene M. Clausen, Esben A. Carlsen, Carsten P. Hansen, Niels Kroman, Seppo W. Langer, Claus Høgdall, Jacob Madsen, Nic Gillings, Carsten H. Nielsen, Thomas L. Klausen, Søren Holm, Annika Loft, Anne K. Berthelsen, Andreas Kjaer
Journal of Nuclear Medicine Dec 2022, 63 (12) 1871-1879; DOI: 10.2967/jnumed.122.264068

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First-in-Humans PET Imaging of Tissue Factor in Patients with Primary and Metastatic Cancers Using 18F-labeled Active-Site Inhibited Factor VII (18F-ASIS): Potential as Companion Diagnostic
Mathias Loft, Camilla Christensen, Malene M. Clausen, Esben A. Carlsen, Carsten P. Hansen, Niels Kroman, Seppo W. Langer, Claus Høgdall, Jacob Madsen, Nic Gillings, Carsten H. Nielsen, Thomas L. Klausen, Søren Holm, Annika Loft, Anne K. Berthelsen, Andreas Kjaer
Journal of Nuclear Medicine Dec 2022, 63 (12) 1871-1879; DOI: 10.2967/jnumed.122.264068
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Keywords

  • Active site inhibited factor VII (ASIS)
  • Tissue Factor
  • PET/CT
  • first-in-humans
  • Phase I clinical trial
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