Christoph Schliemann 1 , Mirjam Gerwing 2 , Hauke Heinzow 3 , Saliha Harrach 1 , Christian Schwöppe 1 , Moritz Wildgruber 2 , Anna A. Hansmeier 1 , Linus Angenendt 1 , Andrew F. Berdel 1 , Ursula Stalmann 1 , Björna Berning 4 , Karsten Kratz-Albers 5 , Kristina Middelberg-Bisping 6 , Stefanie Wiebe 7 , Jörn Albring 1 , Christian Wilms 3 , Wolfgang Hartmann 8 , Eva Wardelmann 8 , Tobias Krähling 2 , Walter Heindel 2 , Joachim Gerss 9 , Eike Bormann 9 , Hartmut Schmidt 3 , Georg Lenz 1 , Torsten Kessler 1 , Rolf M. Mesters 1 , Wolfgang E. Berdel 1 , *
07 June 2020
Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction. Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts. Results: MTD was 3 mg/m 2 tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t 1/2(terminal) of 8 to 9 h without accumulation in daily administrations. Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.