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First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results
Christoph Schliemann1, Mirjam Gerwing2, Hauke Heinzow3
1Department of Medicine A, Hematology, Oncology, University Hospital Muenster, D-48149 Muenster, Germany.
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.
Insights
Truncated tissue factor (tTF) with an NGR-peptide (tTF-NGR) targets CD13 on tumor vasculature, inducing thrombosis. Phase I study showed tTF-NGR is safely applicable, reducing tumor blood flow and causing necrosis.
Area of Science:
- Oncology
- Vascular Biology
- Pharmacology
Background:
- Aminopeptidase N (CD13) is expressed on tumor vasculature and cells.
- Truncated tissue factor fused with an NGR-peptide (tTF-NGR) targets CD13, inducing tumor vascular thrombosis and infarction.
Purpose of the Study:
- To evaluate the safety and efficacy of tTF-NGR in patients with advanced cancer.
- To determine the Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) of tTF-NGR.
Main Methods:
- A Phase I study treated 17 advanced cancer patients with tTF-NGR via central venous infusion over 5 consecutive days with 2-week rest periods.
- Intraindividual dose escalations were permitted, with MTD and DLT established by verification cohorts.
Main Results:
- The MTD was determined to be 3 mg/m² tTF-NGR/day × 5, q day 22.
- The DLT was an isolated, reversible elevation of high-sensitivity Troponin T without clinical sequelae.
- Contrast-enhanced ultrasound and DCE-MRI demonstrated significant tumor-specific blood flow reduction, intratumoral hemorrhage, and necrosis.
- Three reversible thromboembolic events (grade 2) were observed, related to tTF-NGR and other risk factors.
Conclusions:
- The tTF-NGR regimen is safely applicable in advanced cancer patients.
- Imaging confirmed selective reduction of tumor blood flow and induction of intratumoral hemorrhage and necrosis, supporting the drug's mechanism of action.
