563P - First-in-class CD13-targeted tissue factor tTF-NGR in patients with recurrent or refractory malignant tumours: Safety and pharmacokinetic results of a phase I study

Background

Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. We have designed truncated tissue factor (tTF) with a C-terminal peptide (tTF-NGR) binding to CD13 and causing 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-hour infusion, central venous access, 5 consecutive days, 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 x 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs (interpreted as CTCAE grade 3) without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides relevant other risk factors, were observed at dose levels of 5, 4, and 3 mg/m² (one each), and were completely reversible upon anticoagulation. The C_max levels and AUCs revealed a dose-related exposure of the patients to tTF-NGR during the treatment period. Mean peak plasma levels of tTF-NGR in patients treated by a 1-h intravenous infusion for 5 days were generally observed 1 hour after start of dosing. The calculated mean alpha plasma distribution half-life of tTF-NGR at 3 mg/m² was 1.14 hours. tTF-NGR was eliminated with a mean terminal half-life of 8.99 hours. Pharmacokinetic analysis showed no accumulation in daily administrations. There were no responses (RECIST), but some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR. Major and selective inhibition of tumor blood flow was observed by MRI and ultrasound.

Conclusions

tTF-NGR is safely applicable with this regimen. Isolated Troponin T hs elevation occurred as DLT and was interpreted as sensitive early sign for myocardial cell hypoxia, valuable for prevention of clinically relevant side effects. Grade 2 thromboembolic events were reversible by anticoagulation. Pharmacokinetic analysis showed a t_{1/2(terminal)} of 8 to 9h without accumulation in daily administrations. Proof of principle for the mode of action of tTF-NGR could be shown by tumor imaging.

Clinical trial identification

NCT02902237, EudraCT-No.: 2016-003042-85.

Editorial acknowledgement

Legal entity responsible for the study

University Hospital Muenster, Muenster, Germany.

Funding

Deutsche Krebshilfe, Else Kröner-Fresenius Stiftung, Deutsche Forschungsgemeinschaft.

Disclosure

C. Schwöppe: Leadership role, Shareholder/Stockholder/Stock options: ANTUREC Pharmaceuticals GmbH. W.E. Berdel: Leadership role, Shareholder/Stockholder/Stock options: ANTUREC Pharmaceuticals GmbH. All other authors have declared no conflicts of interest.