Original Paper

Journal of Cancer Research and Clinical Oncology

, Volume 139, Issue 3, pp 447-455

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

  • G. SpitaleriAffiliated withIstituto Europeo di Oncologia
  • , R. BerardiAffiliated withClinica di Oncologia Medica, Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I
  • , C. PierantoniAffiliated withClinica di Oncologia Medica, Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I
  • , T. De PasAffiliated withIstituto Europeo di Oncologia
  • , C. NoberascoAffiliated withIstituto Europeo di Oncologia
  • , C. LibbraAffiliated withPhilogen S.p.A.
  • , R. González-IglesiasAffiliated withPhilogen S.p.A.
  • , L. GiovannoniAffiliated withPhilogen S.p.A.
  • , A. TasciottiAffiliated withPhilogen S.p.A.
    • , D. NeriAffiliated withDepartment of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich
    • , H. D. MenssenAffiliated withPhilogen S.p.A.
    • , F. de BraudAffiliated withIstituto Europeo di OncologiaFondazione IRCCS Istituto Nazionale Tumori Email author 

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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.

Keywords

Armed antibody Immunocytokine L19-TNF Phase I/II trial Vascular targeting Vasodisruptive therapy