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

Abstract Purpose L19-TNF is an armed antibody that selectively targets human TNF to extra domain B-fibronectin (EDB) on tumour blood vessels. We performed a phase I/II firstin- 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 to 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 (SD) 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 was reached, allowing for further dose escalation of L19-TNF possibly in combination with chemotherapy.