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.
PURPOSE:L19-TNF is an armed antibody that selectively targets humanTNF 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 cancerpatients 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 cancerpatients 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.
Authors: P Therasse; S G Arbuck; E A Eisenhauer; J Wanders; R S Kaplan; L Rubinstein; J Verweij; M Van Glabbeke; A T van Oosterom; M C Christian; S G Gwyther Journal: J Natl Cancer Inst Date: 2000-02-02 Impact factor: 13.506
Authors: Vanesa Gregorc; Giovanni Citterio; Giordano Vitali; Anna Spreafico; Paola Scifo; Anna Borri; Giovanni Donadoni; Gilda Rossoni; Angelo Corti; Federico Caligaris-Cappio; Alessandro Del Maschio; Antonio Esposito; Francesco De Cobelli; Flavio Dell'Acqua; Antonella Troysi; Paolo Bruzzi; Antonio Lambiase; Claudio Bordignon Journal: Eur J Cancer Date: 2010-01 Impact factor: 9.162
Authors: S Folli; A Pèlegrin; Y Chalandon; X Yao; F Buchegger; D Lienard; F Lejeune; J P Mach Journal: Int J Cancer Date: 1993-03-12 Impact factor: 7.396
Authors: D R Spriggs; M L Sherman; H Michie; K A Arthur; K Imamura; D Wilmore; E Frei; D W Kufe Journal: J Natl Cancer Inst Date: 1988-09-07 Impact factor: 13.506
Authors: Cornelia Halin; Verena Gafner; Maria Elena Villani; Laura Borsi; Alexander Berndt; Hartwig Kosmehl; Luciano Zardi; Dario Neri Journal: Cancer Res Date: 2003-06-15 Impact factor: 12.701