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

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 SUV_max 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 SUV_max 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.