title: The tumour-targeting human L19-IL2 immunocytokine: preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma.
abstract: BACKGROUND
  L19-IL2, a tumour-targeting immunocytokine composed of the recombinant human antibody fragment L19 (specific to the alternatively-spliced EDB domain of fibronectin, a well characterised marker of tumour neo-vasculature) and of human IL2, has demonstrated strong therapeutic activity in animal cancer models. This phase I/II trial was performed to evaluate safety, tolerability, recommended phase II dose (RD) and early signs of activity of L19-IL2.
  
  
  METHODS
  Five cohorts of patients with progressive solid tumours (n=21) received an intravenous infusion of L19-IL2 (from 5 to 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 3 weeks. This treatment cycle was repeated up to six times. In the following expansion phase, patients with metastatic renal cell carcinoma (RCC) (n=12) were treated at the RD of L19-IL2. Clinical data and laboratory findings were analysed for safety, tolerability and activity.
  
  
  RESULTS
  Preclinical studies in rats and monkeys did not raise any safety concerns. The RD was defined to be 22.5 Mio IU IL2 equivalent. Pharmacokinetics of L19-IL2 was dose proportional over the tested range, with a terminal half-life of 2-3h. Toxicities were manageable and reversible with no treatment-related deaths. We observed stable disease in 17/33 patients (51%) and 15/18 with mRCC (83%) after two cycles. Median progression-free survival of RCC patients in the expansion phase of the study was 8 months (1.5-30.5).
  
  
  CONCLUSIONS
  L19-IL2 can be safely and repeatedly administered at the RD of 22.5 Mio IU IL2 equivalent in advanced solid tumours. Preliminary evaluation suggests clinical activity of L19-IL2 in patients with mRCC.
authors.affiliation: Department of Urology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. manfred.johannsen@charite.de
authors.forename: Manfred
authors.initials: M
authors.lastname: Johannsen
authors.forename: Gianluca
authors.initials: G
authors.lastname: Spitaleri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Curigliano
authors.forename: Jan
authors.initials: J
authors.lastname: Roigas
authors.forename: Steffen
authors.initials: S
authors.lastname: Weikert
authors.forename: Carsten
authors.initials: C
authors.lastname: Kempkensteffen
authors.forename: Andreas
authors.initials: A
authors.lastname: Roemer
authors.forename: Christian
authors.initials: C
authors.lastname: Kloeters
authors.forename: Patrik
authors.initials: P
authors.lastname: Rogalla
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pecher
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.forename: Alexander
authors.initials: A
authors.lastname: Berndt
authors.forename: Hartwig
authors.initials: H
authors.lastname: Kosmehl
authors.forename: Eveline
authors.initials: E
authors.lastname: Trachsel
authors.forename: Manuela
authors.initials: M
authors.lastname: Kaspar
authors.forename: Valeria
authors.initials: V
authors.lastname: Lovato
authors.forename: Reinerio
authors.initials: R
authors.lastname: González-Iglesias
authors.forename: Leonardo
authors.initials: L
authors.lastname: Giovannoni
authors.forename: Hans D
authors.initials: HD
authors.lastname: Menssen
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014057:Tomography, X-Ray Computed
chemical_list: D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C554817:L19-IL2 immunocytokine; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins