A phase I study of NGR-TNF, a novel vascular targeting agent, in patients with refractory solid tumors (EORTC 16041)

Abstract

14074 Background: NGR-TNF is a novel agent exploiting a tumour homing peptide (cNGRCG) that selectively targets CD13 that is expressed on the neovasculature of solid tumors. Preclinical data show that its antitumour activity is achieved by a change of vascular permeability (at low doses) and damage of tumour-associated blood vessels (at high doses). This phase I study is being conducted to assess its safety, PK, PD, MTD, and optimal biological dose in patients (pts) with advanced solid tumours. Methods: NGR-TNF was administered once every 3 weeks by a 20 min IV infusion 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 grade 2 toxicity was observed; thereafter a modified Fibonacci schedule was used. PK and PD analysis in blood was performed during the first 4 cycles. DCE-MRI was performed in cycle 1 at baseline and 2 hours after start of the infusion to document modification of the tumour vascularity. Anti-tumour activity was assessed by CT scan every 2 cycles. Results: 45 pts were treated and 133 cycles of treatment completed up to now. 12 DLs have been visited (0.2 to 14.36 μg/m2). One DLT (bronchospasm G 3) was observed at DL4 (1.3 μg/m2) and the DL was extended to 7 pts. As no other DLT was observed, dose escalation was continued. Since then no additional pt experienced dose-limiting toxicity. As 3/18 first pts experienced chills G 2 during injection time, the study was amended and infusion time increased to 1 hour. Since then 1/14 next pts had G 2 chills. Overall most frequently related adverse events reported in the first 34 pts: chills 76%, fever 44%, nausea 20%, constipation 12%, diarrhea 9%, anorexia and hypotension 6%. PK/PD analysis for the plasma levels of TNF-RI and TNF-RII showed a better profile for the 60 min compared with the 20 min infusion. At DL = 1.3 μg/m2 most pts showed a decrease in kep and the number of pixels with a low fraction of kep and Ktrans significantly increased (p<0.05), as seen with other anti- vascular agents. Stable disease was observed in 39% of pts, with a median duration of 11 wks (range 5–36). No responses were observed. Conclusions: NGR-hTNF is well tolerated and some biological activity was observed by DCE-MRI. Study enrollment is ongoing. [Table: see text]