title: Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours.
abstract: BACKGROUND
  NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-alpha) fused to the tumour-homing peptide NGR, a ligand of an aminopeptidase N/CD13 isoform, which is overexpressed on endothelial cells of newly formed tumour blood vessels. NGR-TNF showed a biphasic dose-response curve in preclinical models. This study exploring the low-dose range aimed to define safety and optimal biological dose of NGR-hTNF.
  
  
  METHODS
  Pharmacokinetics, plasma biomarkers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated at baseline and after each cycle in 16 patients enrolled at four doubling-dose levels (0.2-0.4-0.8-1.6 microg/m(2)). NGR-hTNF was given intravenously as 1-h infusion every 3 weeks (q3w). Tumour response was assessed q6w.
  
  
  RESULTS
  Eighty-three cycles (median, 2; range, 1-29) were administered. Most frequent treatment-related toxicity was grade 1-2 chills (69%), occurring during the first infusions. Only one patient treated at 1.6 microg/m(2) had a grade 3 drug-related toxicity (chills and dyspnoea). Both C(max) and AUC increased proportionally with dose. No shedding of soluble TNF-alpha receptors was observed up to 0.8 microg/m(2). Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of K(trans), which was more pronounced at 0.8 microg/m(2). Seven patients (44%) had stable disease for a median time of 5.9 months, including a colon cancer patient who experienced an 18-month progression-free time.
  
  
  CONCLUSIONS
  Based on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 microg/m(2) will be further developed either as single-agent or with standard chemotherapy.
authors.affiliation: Department of Oncology, Istituto Scientifico San Raffaele, Milan, Italy.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gregorc
authors.forename: Giovanni
authors.initials: G
authors.lastname: Citterio
authors.forename: Giordano
authors.initials: G
authors.lastname: Vitali
authors.forename: Anna
authors.initials: A
authors.lastname: Spreafico
authors.forename: Paola
authors.initials: P
authors.lastname: Scifo
authors.forename: Anna
authors.initials: A
authors.lastname: Borri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Donadoni
authors.forename: Gilda
authors.initials: G
authors.lastname: Rossoni
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Del Maschio
authors.forename: Antonio
authors.initials: A
authors.lastname: Esposito
authors.forename: Francesco
authors.initials: F
authors.lastname: De Cobelli
authors.forename: Flavio
authors.initials: F
authors.lastname: Dell'Acqua
authors.forename: Antonella
authors.initials: A
authors.lastname: Troysi
authors.forename: Paolo
authors.initials: P
authors.lastname: Bruzzi
authors.forename: Antonio
authors.initials: A
authors.lastname: Lambiase
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C464839:tumor necrosis factor-alpha, CNGRC fusion protein, human