Animal Safety, Toxicology, and Pharmacokinetic Studies According to the ICH S9 Guideline for a Novel Fusion Protein tTF-NGR Targeting Procoagulatory Activity into Tumor Vasculature: Are Results Predictive for Humans?

Abstract

Background: CD-13 targeted tissue factor tTF-NGR is a fusion protein selectively inducing occlusion of tumor vasculature with resulting tumor infarction. Mechanistic and pharmacodynamic studies have shown broad anti-tumor therapeutic effects in xenograft models. Methods: After successful Good Manufacturing Practice (GMP) production and before translation into clinical phase I, ICH S9 (S6) guideline-conforming animal safety, toxicology, and pharmacokinetic (PK) studies were requested by the federal drug authority in accordance with European and US regulations. Results: These studies were performed in mice, rats, guinea pigs, and beagle dogs. Results of the recently completed clinical phase I trial in end-stage cancer patients showed only limited predictive value of these non-clinical studies for patient tolerability and safety in phase I. Conclusions: Although this experience cannot be generalized, alternative pathways with seamless clinical phase 0 microdosing—phase I dose escalation studies are endorsed for anticancer drug development and translation into the clinic.

Keywords

• non-clinical safety and toxicology studies
• vascular targeting
• fusion protein tTF-NGR
• regulatory requirements for translation of anti-cancer drugs into human trials
• seamless phase 0 micro-dosing and phase I trial concept