OC10 | FROM DESIGN TO CLINICAL PHASE 3 IN ONCOLOGY: CD13-TARGETED TISSUE FACTOR AND TUMOR INFARCTION

W.E. Berdel, C. Schwöppe, C. Brand, K. Hessling, A.F. Berdel, T. Kessler, G. Lenz, R.M. Mesters, C. Schliemann | Department of Medicine A, University Hospital, Muenster, Germany

Introduction and Aim. This overview summarizes the development of CD13-targeted tissue factor (tTF-NGR) from its original design to clinical phase 3 in oncology.

Materials and Methods. A series of targeted tissue factors (TFs) were cloned and biotechnologically produced with various tumor endothelial cell and pericyte targets. They were tested in vitro and in vivo for procoagulatory activity, specific binding, tumor accumulation, vascular occlusion, inhibition of blood flow, therapeutic antitumor effects, and toxicology in rodents and non-rodents and in clinical studies.

Results. The lead compound tTF-NGR showed strong in vitro and in vivo activity, factor X activation, and tumor infarction, growth inhibition, and regression. Its preclinical efficacy was independent of tumor histology (melanoma, lung, breast, sarcoma, and glioblastoma). Combination with cytotoxics such as doxorubicin or trabectedin (T) yielded combinatorial effects. A phase 1 trial in end-stage cancer patients defined the Maximum Tolerated Dose (MTD) as 3 mg/m² IV daily for 5 days, q.d. 22. Dose-limiting toxicities (DLT, grade 3 CTCAE) at higher doses were observed as troponin T hs elevation (early myocardial hypoxia) and reversible thromboembolic events. No grade 4 or 5 events occurred. In a dose-finding cohort of 19 advanced soft-tissue sarcoma patients treated with T plus tTF-NGR, MTD was T 1.5 mg/m² over 24 h (day 1) plus tTF-NGR 1.0 mg/m² IV (days 2–3), every day 22. The recommended starting dose for phase 3 is tTF-NGR 0.5 mg/m² (days 2–3). At this dose, none of six patients had DLTs. The number of cycles per patient (according to RECIST results) were as follows: 2 (PD, progressive disease), 3 (PD), 6 (PD), 12 (SD, stable disease), 14 (PR, partial response), and 14 (SD). All SD patients had tumor shrinkage. Higher tTF-NGR doses or extended schedules led to grade 3 DLTs (troponin T hs rise, N-STEMI, and thromboembolic events), all of which were reversible upon anticoagulation. Again, no grade 4 or 5 toxicities were seen. Pharmacokinetics show more and longer tTF-NGR in the plasma after T, which explains MTD differences between monotherapy and combination therapy. Among 11 L-sarcoma patients completing at least one cycle, the disease control rate (PR plus SD) was 63.6%.

Conclusions. CD13-targeted tTF-NGR demonstrates strong preclinical antitumor efficacy and a manageable safety profile with clinical anti-sarcoma activity when combined with T. A randomized phase 3 trial (1:1, T vs. T plus tTF-NGR) is actively recruiting patients.