title: Phase I and pharmacodynamic study of high-dose NGR-hTNF in patients with refractory solid tumours.
abstract: BACKGROUND
  NGR-hTNF exploits the peptide asparagine-glycine-arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR-hTNF was previously established at 45 μg m(-2) as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol).
  
  
  METHODS
  Four patients entered each of 12 dose levels (n=48; 60-325 μg m(-2)). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (K(trans)) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre- and post-treatment.
  
  
  RESULTS
  Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both C(max) (P<0.0001) and area under the plasma concentration-time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment K(trans) values (P<0.0001), which inversely correlated with NGR-hTNF C(max) (P=0.03) and baseline K(trans) values (P<0.0001). Lower sTNF-R2 levels and greater K(trans) decreases after first cycle were associated with improved survival.
  
  
  CONCLUSIONS
  asparagine-glycine-arginine-hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects.
authors.affiliation: Department of Oncology, Humanitas Cancer Center IRCCS, Rozzano, Italy.
authors.forename: P A
authors.initials: PA
authors.lastname: Zucali
authors.forename: M
authors.initials: M
authors.lastname: Simonelli
authors.forename: F
authors.initials: F
authors.lastname: De Vincenzo
authors.forename: E
authors.initials: E
authors.lastname: Lorenzi
authors.forename: M
authors.initials: M
authors.lastname: Perrino
authors.forename: M
authors.initials: M
authors.lastname: Bertossi
authors.forename: R
authors.initials: R
authors.lastname: Finotto
authors.forename: S
authors.initials: S
authors.lastname: Naimo
authors.forename: L
authors.initials: L
authors.lastname: Balzarini
authors.forename: C
authors.initials: C
authors.lastname: Bonifacio
authors.forename: I
authors.initials: I
authors.lastname: Timofeeva
authors.forename: G
authors.initials: G
authors.lastname: Rossoni
authors.forename: G
authors.initials: G
authors.lastname: Mazzola
authors.forename: A
authors.initials: A
authors.lastname: Lambiase
authors.forename: C
authors.initials: C
authors.lastname: Bordignon
authors.forename: A
authors.initials: A
authors.lastname: Santoro
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C464839:tumor necrosis factor-alpha, CNGRC fusion protein, human