PURPOSE: This phase I trial investigating the vascular targeting agent NGR-hTNF aimed to determine the (a) dose-limiting toxicities, (b) maximum tolerated dose (MTD), (c) pharmacokinetics and pharmacodynamics, (d) vascular response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (e) preliminary clinical activity in solid tumors. EXPERIMENTAL DESIGN: NGR-hTNF was administered once every 3 weeks by a 20- to 60-minute i.v. infusion to cohorts of three to six patients with solid tumors in escalating doses. Pharmacokinetic and pharmacodynamic analyses in blood were done during the first four cycles. DCE-MRI was done in cycle 1 at baseline and 2 hours after the start of the infusion. RESULTS: Sixty-nine patients received a total of 201 cycles of NGR-hTNF (0.2-60 microg/m(2)). Rigors and fever were the most frequently observed toxicities. Four dose-limiting toxicities were observed (at doses of 1.3, 8.1, and 60 microg/m(2)), of which three were infusion related. The MTD was 45 microg/m(2). The mean apparent terminal half-life ranged from 0.963 to 2.08 hours. DCE-MRI results of tumors showed a vascular response to NGR-hTNF. No objective responses were observed, but 27 patients showed stable disease with a median duration of 12 weeks. CONCLUSIONS: NGR-hTNF was well tolerated. The MTD was 45 microg/m(2) administered in 1 hour once every 3 weeks. DCE-MRI results showed the antivascular effect of NGR-hTNF. These findings call for further research for defining the optimal biological dose and clinical activity of NGR-hTNF as a single agent or in combination with cytotoxic drugs.
PURPOSE: This phase I trial investigating the vascular targeting agent NGR-hTNF aimed to determine the (a) dose-limiting toxicities, (b) maximum tolerated dose (MTD), (c) pharmacokinetics and pharmacodynamics, (d) vascular response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (e) preliminary clinical activity in solid tumors. EXPERIMENTAL DESIGN:NGR-hTNF was administered once every 3 weeks by a 20- to 60-minute i.v. infusion to cohorts of three to six patients with solid tumors in escalating doses. Pharmacokinetic and pharmacodynamic analyses in blood were done during the first four cycles. DCE-MRI was done in cycle 1 at baseline and 2 hours after the start of the infusion. RESULTS: Sixty-nine patients received a total of 201 cycles of NGR-hTNF (0.2-60 microg/m(2)). Rigors and fever were the most frequently observed toxicities. Four dose-limiting toxicities were observed (at doses of 1.3, 8.1, and 60 microg/m(2)), of which three were infusion related. The MTD was 45 microg/m(2). The mean apparent terminal half-life ranged from 0.963 to 2.08 hours. DCE-MRI results of tumors showed a vascular response to NGR-hTNF. No objective responses were observed, but 27 patients showed stable disease with a median duration of 12 weeks. CONCLUSIONS:NGR-hTNF was well tolerated. The MTD was 45 microg/m(2) administered in 1 hour once every 3 weeks. DCE-MRI results showed the antivascular effect of NGR-hTNF. These findings call for further research for defining the optimal biological dose and clinical activity of NGR-hTNF as a single agent or in combination with cytotoxic drugs.
Authors: James P B O'Connor; Alan Jackson; Geoff J M Parker; Caleb Roberts; Gordon C Jayson Journal: Nat Rev Clin Oncol Date: 2012-02-14 Impact factor: 66.675
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Authors: A Santoro; T Pressiani; G Citterio; G Rossoni; G Donadoni; F Pozzi; L Rimassa; N Personeni; S Bozzarelli; G Rossoni; S Colombi; F G De Braud; F Caligaris-Cappio; A Lambiase; C Bordignon Journal: Br J Cancer Date: 2010-08-17 Impact factor: 7.640
Authors: P A Zucali; M Simonelli; F De Vincenzo; E Lorenzi; M Perrino; M Bertossi; R Finotto; S Naimo; L Balzarini; C Bonifacio; I Timofeeva; G Rossoni; G Mazzola; A Lambiase; C Bordignon; A Santoro Journal: Br J Cancer Date: 2012-11-20 Impact factor: 7.640
Authors: D Lorusso; G Scambia; G Amadio; A di Legge; A Pietragalla; R De Vincenzo; V Masciullo; M Di Stefano; G Mangili; G Citterio; M Mantori; A Lambiase; C Bordignon Journal: Br J Cancer Date: 2012-05-29 Impact factor: 7.640