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

G. Spitaleri, 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

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)447-455
Number of pages9
JournalJournal of Cancer Research and Clinical Oncology
Volume139
Issue number3
DOIs
Publication statusPublished - Mar 2013

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Monoclonal Antibodies
Cytokines
Neoplasms
Proteins
Vascular Tissue Neoplasms
Safety
Chills
Hydroxyindoleacetic Acid
Maximum Tolerated Dose
Lymphocyte Subsets
Combination Drug Therapy
Serum
Fibronectins
Nausea
Antibody Formation
Vomiting
Half-Life
Colorectal Neoplasms
Appointments and Schedules
Neoplasm Metastasis

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours. / Spitaleri, G.; Berardi, R.; Pierantoni, C.; De Pas, T.; Noberasco, C.; Libbra, C.; González-Iglesias, R.; Giovannoni, L.; Tasciotti, A.; Neri, D.; Menssen, H. D.; De Braud, F.

In: Journal of Cancer Research and Clinical Oncology, Vol. 139, No. 3, 03.2013, p. 447-455.

Research output: Contribution to journalArticle

Spitaleri, G. ; Berardi, R. ; Pierantoni, C. ; De Pas, T. ; Noberasco, C. ; Libbra, C. ; González-Iglesias, R. ; Giovannoni, L. ; Tasciotti, A. ; Neri, D. ; Menssen, H. D. ; De Braud, F. / Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours. In: Journal of Cancer Research and Clinical Oncology. 2013 ; Vol. 139, No. 3. pp. 447-455.
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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.",
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AU - Spitaleri, G.

AU - Berardi, R.

AU - Pierantoni, C.

AU - De Pas, T.

AU - Noberasco, C.

AU - Libbra, C.

AU - González-Iglesias, R.

AU - Giovannoni, L.

AU - Tasciotti, A.

AU - Neri, D.

AU - Menssen, H. D.

AU - De Braud, F.

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N2 - 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.

AB - 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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