Cancers (Jun 2020)

First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study

  • Christoph Schliemann,
  • Mirjam Gerwing,
  • Hauke Heinzow,
  • Saliha Harrach,
  • Christian Schwöppe,
  • Moritz Wildgruber,
  • Anna A. Hansmeier,
  • Linus Angenendt,
  • Andrew F. Berdel,
  • Ursula Stalmann,
  • Björna Berning,
  • Karsten Kratz-Albers,
  • Kristina Middelberg-Bisping,
  • Stefanie Wiebe,
  • Jörn Albring,
  • Christian Wilms,
  • Wolfgang Hartmann,
  • Eva Wardelmann,
  • Tobias Krähling,
  • Walter Heindel,
  • Joachim Gerss,
  • Eike Bormann,
  • Hartmut Schmidt,
  • Georg Lenz,
  • Torsten Kessler,
  • Rolf M. Mesters,
  • Wolfgang E. Berdel

DOI
https://doi.org/10.3390/cancers12061488
Journal volume & issue
Vol. 12, no. 6
p. 1488

Abstract

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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/m2 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 t1/2(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.

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