Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours

作者：Gregorc Vanesa; Citterio Giovanni; Vitali Giordano; Spreafico Anna; Scifo Paola; Borri Anna; Donadoni Giovanni; Rossoni Gilda; Corti Angelo; Caligaris Cappio Federico; Del Maschio Alessandro; Esposito Antonio; De Cobelli Francesco; Dell'Acqua Flavio; Troysi Antonella; Bruzzi Paolo; Lambiase Antonio; Bordignon Claudio^*

来源：European Journal of Cancer, 2010, 46(1): 198-206.

DOI：10.1016/j.ejca.2009.10.005

• NGR-hTNF
• Phase I
• Solid tumours

Background: NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-alpha) fused to the tumour-homing peptide NGR, a ligand of an aminopeptidase N/CD13 isoform, which is overexpressed on endothelial cells of newly formed tumour blood vessels. NGR-TNF showed a biphasic dose-response curve in preclinical models. This study exploring the low-dose range aimed to define safety and optimal biological dose of NGR-hTNF.
Patients and methods: Pharmacokinetics, plasma biomarkers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated at baseline and after each cycle in 16 patients enrolled at four doubling-dose levels (0.2-0.4-0.8-1.6 mu g/m(2)). NGR-hTNF was given intravenously as 1-h infusion every 3 weeks (q3w). Tumour response was assessed q6w.
Results: Eighty-three cycles (median, 2; range, 1-29) were administered. Most frequent treatment-related toxicity was grade 1-2 chills (69%), occurring during the first infusions. Only one patient treated at 1.6 mu g/m(2) had a grade 3 drug-related toxicity (chills and dyspnoea). Both C(max) and AUC increased proportionally with dose. No shedding of soluble TNF-alpha receptors was observed up to 0.8 mu g/m(2). Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of K(trans), which was more pronounced at 0.8 mu g/m(2). Seven patients (44%) had stable disease for a median time of 5.9 months, including a colon cancer patient who experienced an 18-month progression-free time.
Conclusion: Based on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 mu g/m(2) will be further developed either as single-agent or with standard chemotherapy.

• 出版日期2010-1