Phase I and DCE-MRI evaluation of NGR-TNF, a novel vascular targeting agent, in patients with solid tumors (EORTC 16041)

Abstract

3521 Background: NGR-TNF is a novel agent exploiting a tumor homing peptide (cNGRCG) that selectively targets CD13 that is expressed on tumor neovasculature. Preclinical data show that its antitumor activity is achieved by a change of vascular permeability (at low doses) and damage of tumor-associated blood vessels (at high doses). This phase I study was conducted to assess its safety, PK, PD, MTD, and optimal biological dose in patients (pts) with advanced solid tumors. Methods: NGR-TNF was administered once every 3 weeks by an IV infusion in 20 min in the first 18 pts and in 1 hr IV infusion in the other pts, to cohorts of 3–6 pts. The starting dose was 0.2 μg/m2. Dose escalation was performed with a doubling of the dose until G2 toxicity was observed; thereafter a modified Fibonacci schedule was used. DCE-MRI was performed in Cy 1 at baseline and 2 hours after start of the infusion at each DL. Results: 70 pts were treated with in total 179 Cy (1–12). 17 DLs have been visited (0.2 to 60 μg/m2). 4 DLTs (bronchospasm at 1.3 μg/m2; abdominal pain with hypotension at 8.1 μg/m2; dyspnea and acute infusion reaction at 60 μg/m2 - all G3) were observed. The MTD was 45 μg/m2 with no DLT in 9 pts. Most frequently related adverse events were chills (81%) and fever (58%). No objective responses were observed, 21 pts had SD. DCE-MRI data of 31 pts were available. At dose-levels ≥1.3 μg/m2 the majority of pts showed a decrease in Ktrans compared to baseline. Although the mean kep and Ktrans were not significantly different at baseline and follow-up, at dose-levels ≥1.3 μg/m2 the mean Ktrans significantly decreased (.015 vs .012 a.u. s-1; p <.05). For all DLs, the mean number of pixels with a low fraction of kep and Ktrans significantly increased (p<0.01), as seen with other anti- vascular agents. The change in Ktrans was not related with DL. AUC and Cmax increased dose proportional. TNF-RI and II increased with dose, but a plateau was seen ≥25.4 μg/m2. A dose-dependent increase of MIP-1β and MCP- 1 and decrease of EGF was seen. Generation of anti-NGR-TNF antibodies was not observed. Conclusions: NGR-hTNF is well tolerated; the MTD is 45 μg/m2. The DCE-MRI results suggest an anti-vascular effect of NGR-TNF. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MolMed S.p.A. MolMed S.p.A.