Phase II Study of Asparagine-Glycine-Arginine–Human Tumor Necrosis Factor , a Selective Vascular Targeting Agent, in Previously Treated Patients With Malignant Pleural Mesothelioma Vanesa Gregorc, Paolo A. Zucali, Armando Santoro, Giovanni L. Ceresoli, Giovanni Citterio, Tommaso M. De Pas, Nicoletta Zilembo, Fabio De Vincenzo, Matteo Simonelli, Gilda Rossoni, Anna Spreafico, Maria Grazia Vigano `, Floriana Fontana, Filippo G. De Braud, Emilio Bajetta, Federico Caligaris-Cappio, Paolo Bruzzi, Antonio Lambiase, and Claudio Bordignon From the Department of Oncology, Isti- tuto Scientifico San Raffaele, Universita ` Vita-Salute San Raffaele; MolMed; Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Clinical Pharmacology and New Drugs, Istituto Europeo di Oncologia; Division of Clini- cal Pharmacology and New Drugs, Isti- tuto Europeo di Oncologia; and Department of Oncology, IRCCS Fonda- zione Istituto Nazionale dei Tumori, Milan; Clinical Epidemiology Unit, Isti- tuto Nazionale per la Ricerca sul Cancro, Genoa; and Department of Oncology, Istituto Clinico Humanitas, Rozzano, Italy. Submitted December 2, 2009; accepted February 22, 2010; published online ahead of print at www.jco.org on April 20, 2010. Supported by MolMed. V.G. and P.A.Z. contributed equally to this work. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Claudio Bordignon, MD; Via Olgettina, 60; 20132 Milan, Italy; e-mail: claudio .bordignon@hsr.it. © 2010 by American Society of Clinical Oncology 0732-183X/10/2815-2604/$20.00 DOI: 10.1200/JCO.2009.27.3649 A B S T R A C T Purpose NGR-hTNF consists of human tumor necrosis factor  (hTNF-) fused to the tumor-homing peptide asparagine-glycine-arginine (NGR) able to selectively bind an aminopeptidase N isoform overex- pressed on tumor blood vessels. Hypervascularity is a prominent and poor-prognosis feature of malignant pleural mesothelioma (MPM). Currently, there are no standard options for patients with MPM who are failing a front-line pemetrexed-based regimen. We explored safety and efficacy of NGR-hTNF in this setting. Patients and Methods Eligible patients had radiologically documented tumor progression and performance status  2. Primary study aim was progression-free survival (PFS). NGR-hTNF 0.8 g/m 2 was given intrave- nously every 3 weeks. A subsequent cohort of patients received 0.8 g/m 2 on a weekly basis. Results In the triweekly cohort (n = 43), only one grade 3 drug-related toxicity was noted, and the most common grades 1 to 2 were short-lived chills (71%). The median PFS was 2.8 months (95% CI, 2.3 to 3.3 months). Nineteen patients (44%) had disease control (one had partial response, and 18 had stable diseases) and experienced a median progression-free time of 4.4 months. In the weekly cohort (n = 14), there was no higher toxicity, and median PFS was 3.0 months (95% CI, 1.9 to 4.1 months). Seven patients (50%) had disease control (all stable diseases) and had a median progression-free interval of 9.1 months. In the overall study population (N = 57), median PFS was 2.8 months. Median progression-free time was 4.7 months in twenty-six patients (46%) who achieved disease control. Median survival was 12.1 months. Conclusion The tolerability and disease control of NGR-hTNF 0.8 g/m 2 weekly warrant additional evaluation in patients with advanced MPM. J Clin Oncol 28:2604-2611. © 2010 by American Society of Clinical Oncology INTRODUCTION Since its discovery, 1 tumor necrosis factor  (TNF- ) has shown a powerful antitumor activity, which is mainly mediated through apoptosis of tumor en- dothelial cells initiated by clustering of death domain– containing receptors and leading to cas- pase activation. 2 Disappointingly, the early-stage clinical devel- opment was characterized by severe toxicities when TNF- was administered systemically, when the maximum-tolerated dose (MTD) was at least 10- fold lower than the effective dose in preclinical models. 2-8 More recently, the locoregional delivery by isolated limb or hepatic perfusion of high doses of TNF- combined with chemotherapy was associ- ated with high response rates in patients with mela- noma or sarcoma and was associated with regression of hepatic cancers confined to liver. 2,9-12 With an aim to exploit a ligand-directed vascular-targeting approach, NGR-hTNF was pre- pared by fusing the N terminal of TNF- with the C terminal of the cyclic tumor-homing peptide NGR (ie, asparagine-glycine-arginine). This peptide is a selective ligand of an aminopeptidase N/CD13 iso- form overexpressed by endothelial cells of most solid JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 28  NUMBER 15  MAY 20 2010 2604 © 2010 by American Society of Clinical Oncology Downloaded from ascopubs.org by 3.81.109.30 on June 18, 2022 from 003.081.109.030 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.