Vascular Effects Of The Vascular Targeting Agent Ngr-Htnf In Patients (Pts) With Advanced Solid Cancer: A Dynamic Contrast-Enhanced Magnetic Resonance Imaging (Dce-Mri) Eortc Study.

e13525 Background: Vascular targeted TNF (NGR-hTNF) has antivascular properties. In a recent phase I study (EORTC 16041) it was not possible to select an optimal biological dose of NGR-hTNF from DCE-MRI measurements. We hypothesized this could be due to: (1) insufficient reproducibility of DCE-MRI; (2) non-specific vascular targeting of NGR-hTNF; (3) interference of vessel maturation with anti-vascular effects of NGR-hTNF (4) interference of pharmacodynamic (PD) effects with anti-vascular effects of NGR-hTNF. Methods: DCE-MRI analyses were performed at baseline and two hours after the first administration of NGR-hTNF in 31 cancer pts treated in the phase I study. Reproducibility was determined in 5 non-treated pts with liver metastases. Mean values of kep and Ktrans were calculated and histogram analyses were performed for metastases and healthy liver tissue. Specificity of vascular targeting was assessed by comparing results in metastases and healthy liver tissue. As a surrogate measure of vascular maturation, we assessed pretreatment tumor sizes and correlated these with DCE-MRI results. PD effects of NGR-hTNF were measured by the kinetics of soluble TNF receptors (sTNF-R). Results: Reproducibility of DCE-MRI was adequate, although superior in metastases compared to healthy liver tissue. Mean DCE-MRI parameters did not significantly change after NGR-hTNF administration, but histogram analyses showed significant changes in metastases and healthy liver tissue in some pts. The antivascular effect of NGR-hTNF was larger in smaller tumors, which have less mature vasculature. sTNF-R increased in a dose-dependent manner which could partly explain the failure of DCE-MRI to predict the optimal biological dose. Conclusions: The inability of DCE-MRI to determine the optimal biological dose of NGR-hTNF was not due to inadequate reproducibility, but most likely due to a combination of: (i) different profiles of vascular effects of NGR-hTNF in tumors and healthy liver tissue, (ii) dependency of the antivascular effect of NGR-hTNF on tumor vessel maturation and (iii) the shedding kinetics of soluble TNFα− R. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MolMed