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Clinical Trial
. 2013 Mar;139(3):447-55.
doi: 10.1007/s00432-012-1327-7. Epub 2012 Nov 17.

Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours

G Spitaleri  1 , R Berardi, C Pierantoni, T De Pas, C Noberasco, C Libbra, R González-Iglesias, L Giovannoni, A Tasciotti, D Neri, H D Menssen, F de Braud
Affiliations
Clinical Trial

Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours

G Spitaleri et al. J Cancer Res Clin Oncol. 2013 Mar.

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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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
5-HTAA plasma levels after L19-TNF application. Li-heparin plasma samples from study patients taken at baseline at pre-set time points after L19-TNF application were analysed for the concentration of 5-HIAA (5-hydroxy-indolamino-acid) as an indirect marker of blood vessel damage. Three classes of patients were identified, and a paradigmatic 5-HIAA of one plasma curve over time of one typical patient is depicted: a patient with a high (a), a moderate (b) or no (c) increase in 5-HIAA plasma levels over baseline after L19-TNF infusion
Fig. 2
Fig. 2
Serum concentration (Cmax) of L19-TNF in dose cohorts of study patients as measured with a TNF assay and a L19-TNF fusion protein assay. Venous blood samples were collected repeatedly from all study patients during week 1 of cycle 1 and analysed for L19-TNF concentration using 2 different assays: an assay to detect TNF (both untargeted and L19-TNF) and a fusion protein assay to detect only intact L19-TNF. The geometric means of the Cmax for each cohort of patients (C1–C6) is depicted for the TNF (top) and L19-TNF assay (bottom), both detecting serum L19-TNF
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