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.
BACKGROUND:CD-13 targeted tissue factortTF-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 cancerpatients 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.
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Keywords:
fusion protein tTF-NGR; non-clinical safety and toxicology studies; regulatory requirements for translation of anti-cancer drugs into human trials; seamless phase 0 micro-dosing and phase I trial concept; vascular targeting
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