title: Phase I/II study of the tumour-targeting human monoclonal antibody-cytokine fusion protein L19-TNF in patients with advanced solid tumours.
abstract: OBJECTIVE
  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.
authors.affiliation: Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Spitaleri
authors.forename: R
authors.initials: R
authors.lastname: Berardi
authors.forename: C
authors.initials: C
authors.lastname: Pierantoni
authors.forename: T
authors.initials: T
authors.lastname: De Pas
authors.forename: C
authors.initials: C
authors.lastname: Noberasco
authors.forename: C
authors.initials: C
authors.lastname: Libbra
authors.forename: R
authors.initials: R
authors.lastname: González-Iglesias
authors.forename: L
authors.initials: L
authors.lastname: Giovannoni
authors.forename: A
authors.initials: A
authors.lastname: Tasciotti
authors.forename: D
authors.initials: D
authors.lastname: Neri
authors.forename: H D
authors.initials: HD
authors.lastname: Menssen
authors.forename: F
authors.initials: F
authors.lastname: de Braud
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry; D015331:Cohort Studies; D016207:Cytokines / Q000008:administration & dosage / Q000737:chemistry; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; C558733:L19mTNFalpha protein; D011993:Recombinant Fusion Proteins