Phase I Study Of Ngr-Htnf Administered At High Doses In Refractory Patients With Solid Tumors.

e13091 Background: NGR-hTNF is a vascular targeting agent exploiting a tumor homing peptide (NGR) that selectively binds an aminopeptidase N overexpressed on tumor blood vessels. Previously, a phase I trial testing doses ranging from 0.2 to 60 μg/m2 established the maximum tolerated dose (MTD) of NGR-hTNF at 45 μg/m2 when given as 1-h infusion every 3 weeks (q3w), with dose-limiting toxicity (DLT) being characterized by transient infusion-time related grade 3 reactions. Here, we report further dose escalation by using both longer infusion time and mild premedication. Methods: Patients (pts) with refractory solid tumors received NGR-hTNF given at 60, 80, 100, and 125 μg/m2 as 2-h infusion q3w. Acetaminophen 1,000 mg was given before dosing. Four pts for each dose level (DL) were planned to be enrolled. Any drug-related grade 3 or 4 toxicity was deemed as DLT. Plasma samples for pharmacokinetics and pharmacodynamics (soluble TNF-receptors, sTNF-R1 and -R2) were tested over the first 3 cycles. To assess the biologic effects on tumor vascularity, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed before and on treatment. Results: 12 pts (median age: 65 years, range, 37-71; PS 0/1: 7/5) with a variety of solid tumors were enrolled at the first 3 DLs and were assessed over 32 cycles (range, 1-6). The median number of prior treatment lines was 3 (range, 1-5). No DLTs were recorded at 60 (n=4), 80 (n=4), and 100 μg/m2 (n=4). Most drug related toxicities were grade 1 chills experienced by 7 pts (58%) over 16 cycles (50%). One grade 2 vomiting was noted at the highest DL explored. Both Cmaxand AUC increased dose-proportionally (p=0.0001). The levels of sTNF-R2 were significantly higher than those of sTNF-R1 (p=0.0001). However, the mean changes vs baseline did not significantly differ across DLs (p=0.18 for R1 and p=0.13 for R2), thus suggesting a plateau in the shedding kinetics. By DCE-MRI assessment, decreases in both the volume transfer coefficient (Ktrans) and the initial area under the contrast agent concentration time curve (IAUGC) were detectable in all DLs. Conclusions: NGR-hTNF can be safely escalated at doses higher than the MTD by using longer infusion time and mild premedication. Further dose escalation is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MolMed