Cancer Therapy: Clinical Phase I Clinical and Magnetic Resonance Imaging Study of the Vascular Agent NGR-hTNF in Patients with Advanced Cancers (European Organization for Research and Treatment of Cancer Study 16041) Hanneke W.M. van Laarhoven 1 , Walter Fiedler 4 , Ingrid M.E. Desar 1 , Jack J.A. van Asten 3 , Sandrine Marréaud 5 , Denis Lacombe 5 , Anne-Sophie Govaerts 5 , Jan Bogaerts 5 , Peter Lasch 4 , Johanna N.H. Timmer-Bonte 1,2 , Antonio Lambiase 6 , Claudio Bordignon 6 , Cornelis J.A. Punt 1 , Arend Heerschap 3 , and Carla M.L. van Herpen 1 Abstract 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 pharmacody- namics, (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 μg/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 μg/m 2 ), of which three were infusion related. The MTD was 45 μg/m 2 . The mean apparent terminal half-life ranged from 0.963 to 2.08 hours. DCE-MRI results of tumors showed a vas- cular response to NGR-hTNF. No objective responses were observed, but 27 patients showed stable dis- ease with a median duration of 12 weeks. Conclusions: NGR-hTNF was well tolerated. The MTD was 45 μg/m 2 administered in 1 hour once every 3 weeks. DCE-MRI results showed the antivascular effect of NGR-hTNF. These findings call for fur- ther research for defining the optimal biological dose and clinical activity of NGR-hTNF as a single agent or in combination with cytotoxic drugs. Clin Cancer Res; 16(4); 1315–23. ©2010 AACR. Tumor necrosis factor α (TNFα) is a cytokine well known for its cytostatic and cytotoxic properties, immuno- modulatory activities, and selective obstruction and dam- age of tumor-associated blood vessels. TNFα increases vascular permeability, possibly by disrupting the α v β 3 integrin–mediated endothelial cell adhesion (1), and kills tumor-associated endothelial cells (2). It has been sug- gested that synergy between TNFα and cytotoxic treatment is based on improved drug delivery to tumors due to vas- cular changes induced by TNFα. A clinical proof of concept was shown in studies of isolated limb perfusion in patients with melanoma and sarcoma (3, 4). However, systemic ad- ministration of TNFα is precluded by severe side effects, es- pecially flu-like symptoms, hemodynamic insufficiency, and hepatic toxicity (5, 6). Targeted delivery of TNFα to the tumor could circum- vent the toxicity of systemic administration of TNFα. By coupling the tumor-homing peptide CNGRC, a ligand of a CD13 isoform overexpressed by tumor neovasculature, to TNFα (NGR-hTNF), the selective delivery of TNFα to the tumor can be achieved (7). In murine tumor models, low doses of NGR-hTNF showed greater inhibition of tu- mor growth compared with untargeted TNFα adminis- tered as single agent. It was active either at low doses (0.01-0.1 ng) or at high doses (1,000-10,000 ng), suggest- ing a bell-shaped dose-response curve. Moreover, low doses of NGR-hTNF enhanced the antitumor activity of chemotherapy, indicating a synergistic effect, without in- creasing systemic toxicity (8). TNFα exerts its effects by binding to two types of recep- tors, TNF-RI and TNF-RII, which are present on nearly all mammalian cells (9). After administration of TNFα,a Authors' Affiliations: Departments of 1 Medical Oncology, 2 Pulmonary Diseases, and 3 Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 4 Universitäts-Krankenhaus Hamburg-Eppendorf, Hamburg, Germany; 5 European Organization for Research and Treatment of Cancer Headquarters, Brussels, Belgium; and 6 MolMed, Milan, Italy Corresponding Author: Hanneke W.M. van Laarhoven, Department of Medical Oncology 452, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. Phone: 31-24-361- 03-53; Fax: 31-24-254-07-88; E-mail: h.vanlaarhoven@onco.umcn.nl. doi: 10.1158/1078-0432.CCR-09-1621 ©2010 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 1315 Research. on May 21, 2020. © 2010 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst February 15, 2010; DOI: 10.1158/1078-0432.CCR-09-1621