ORIGINAL PAPER Phase I/II study of the tumour-targeting human monoclonal antibody–cytokine fusion protein L19-TNF in patients with advanced solid tumours G. Spitaleri • R. Berardi • C. Pierantoni • T. De Pas • C. Noberasco • C. Libbra • R. Gonza ´lez-Iglesias • L. Giovannoni • A. Tasciotti • D. Neri • H. D. Menssen • F. de Braud Received: 14 September 2012 / Accepted: 24 September 2012 / Published online: 17 November 2012 Ó Springer-Verlag Berlin Heidelberg 2012 Abstract Purpose L19-TNF is an armed antibody that selectively targets human TNF to extra domain B-fibronectin on tumour blood vessels. We performed a phase I/II first-in- man trial with L19-TNF monotherapy in metastatic solid cancer patients to study safety and signs of clinical activity. Methods Six cohorts of patients were treated with increasing (1.3–13 lg/kg) doses of intravenous L19-TNF on day 1, 3, and 5 of repeated 3-weekly cycles, and 12 colorectal cancer patients were treated at 13 lg/kg. PK, antibody formation, changes in lymphocyte subsets, 5-HIAA plasma levels as well as safety and clinical activity were analysed. Results Thirty-four patients received at least one L19- TNF dose. The serum half-life of L19-TNF at 13 lg/kg was 33.6 min, and maximum peak serum concentration was 73.14 lg/L. Mild chills, nausea and vomiting but no haemato- or unexpected toxicity were observed. Grade 3 lumbar pain in bone metastasis was the only dose-limiting toxicity found in one patient. Objective tumour responses were not detected. Transient stable disease occurred in 19 of 31 evaluable patients. Conclusions Intravenous L19-TNF on day 1, 3, and 5 of a 3-weekly schedule was safe up to 13 lg/kg, but did not result in objective tumour responses. The maximally tol- erated dose (MTD) was not reached, allowing for further dose escalation of L19-TNF possibly in combination with chemotherapy. Keywords Armed antibody Á Immunocytokine Á L19-TNF Á Phase I/II trial Á Vascular targeting Á Vasodisruptive therapy Introduction Tumour necrosis factor (TNF) is a naturally occurring vasodisruptive cytokine. It induces apoptosis of endothelial cell in newly formed blood vessels and haemorrhagic tumour necrosis in animal models and in extremity mela- noma patients undergoing isolated limb perfusion (ILP) (Lejeune et al. 2006; Carswell et al. 1975). Preclinical studies showed that TNF rapidly increases permeability of tumour blood vessels and decreases the interstitial fluid pressure of tumour tissues (Brett et al. 1989), leading to an increased uptake of concomitantly applied anti-cancer H. D. Menssen and F. de Braud contributed equally to this work. Electronic supplementary material The online version of this article (doi:10.1007/s00432-012-1327-7) contains supplementary material, which is available to authorized users. G. Spitaleri Á T. De Pas Á C. Noberasco Á F. de Braud Istituto Europeo di Oncologia, Milan, Italy R. Berardi Á C. Pierantoni Clinica di Oncologia Medica, Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I, Ancona, Italy C. Libbra Á R. Gonza ´lez-Iglesias Á L. Giovannoni Á A. Tasciotti Á H. D. Menssen Philogen S.p.A., La Lizza 7, 53100 Siena, Italy e-mail: hansmenssen@me.com D. Neri Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli-Str. 10, 8093 Zurich, Switzerland F. de Braud (&) Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy e-mail: Filippo.DeBraud@istitutotumori.mi.it 123 J Cancer Res Clin Oncol (2013) 139:447–455 DOI 10.1007/s00432-012-1327-7