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 μg/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 μg/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 μg/kg was 33.6 min, and maximum peak serum concentration was 73.14 μg/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 μg/kg, but did not result in objective tumour responses. The maximally tolerated dose (MTD) was not reached, allowing for further dose escalation of L19-TNF possibly in combination with chemotherapy.
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Acknowledgments
We are grateful to Dana Rogler and Fabio Vecchio for their excellent support in monitoring the study and data management, to Giulia Zigon for the excellent statistical analyses, and to Veronica Brunelli and Fabiana Marcucci, who as study nurses empathically took care of our study patients, as well as to our patients for participating in this trial. Finally, we are indebted to Dr. Azzurra Onofri, Ancona, for his valuable contributions to the trial as sub-investigator.
Conflict of interest
This study was sponsored by Philogen S.p.A, Siena, Italy, EU. Gianluca Spitaleri, Rossana Berardi, Chiara Pierantoni, Tommaso De Pas and Cristina Noberasco declare no conflicting financial interests. Filippo de Braud served as a Medical Advisor for Philogen. Chiara Libbra, Reinerio González-Iglesias, Leonardo Giovannoni, Annaelisa Tasciotti and Hans D. Menssen are employees of Philogen. Daio Neri is a co-founder and owns stocks of Philogen.
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H. D. Menssen and F. de Braud contributed equally to this work.
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Spitaleri, G., Berardi, R., Pierantoni, C. et al. Phase I/II study of the tumour-targeting human monoclonal antibody–cytokine fusion protein L19-TNF in patients with advanced solid tumours. J Cancer Res Clin Oncol 139, 447–455 (2013). https://doi.org/10.1007/s00432-012-1327-7
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DOI: https://doi.org/10.1007/s00432-012-1327-7