title: Phase I study of NGR-hTNF, a selective vascular targeting agent, in combination with cisplatin in refractory solid tumors.
abstract: OBJECTIVE
  NGR-hTNF exploits the tumor-homing peptide asparagine-glycine-arginine (NGR) for selectively targeting TNF-α to an aminopeptidase N overexpressed on cancer endothelial cells. Preclinical synergism with cisplatin was displayed even at low doses. This study primarily aimed to explore the safety of low-dose NGR-hTNF combined with cisplatin in resistant/refractory malignancies. Secondary aims included pharmacokinetics (PKs), pharmacodynamics, and activity.
  
  
  METHODS
  NGR-hTNF was escalated using a doubling-dose scheme (0.2-0.4-0.8-1.6 μg/m(2)) in combination with fixed-dose of cisplatin (80 mg/m(2)), both given intravenously once every three weeks. PKs and circulating TNF-receptors (sTNF-Rs) were assessed over the first three cycles.
  
  
  RESULTS
  Globally, 22 patients (12 pretreated with platinum) received a range of one to ten cycles. Consistently with the low-dose range tested, maximum-tolerated dose was not reached. No dose-limiting toxicities (DLTs) were observed at 0.2 (n = 4) and 0.4 μg/m(2) (n = 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 μg/m(2). This dose cohort was expanded to six patients without further DLTs. No DLTs were noted also at 1.6 μg/m(2) (n = 3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 μg/m(2). At the dose level of 0.8 μg/m(2), expanded to 12 patients for activity assessment, a platinum-pretreated lung cancer patient achieved a partial response lasting more than six months and five patients maintained stable disease for a median time of 5.9 months.
  
  
  CONCLUSIONS
  The combination of NGR-hTNF 0.8 μg/m(2) with cisplatin 80 mg/m(2) showed favorable toxicity profile and promising antitumor activity.
authors.affiliation: Department of Oncology, Istituto Scientifico San Raffaele, Milan, Italy.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gregorc
authors.forename: Filippo G
authors.initials: FG
authors.lastname: De Braud
authors.forename: Tommaso M
authors.initials: TM
authors.lastname: De Pas
authors.forename: Roberto
authors.initials: R
authors.lastname: Scalamogna
authors.forename: Giovanni
authors.initials: G
authors.lastname: Citterio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Milani
authors.forename: Sabrina
authors.initials: S
authors.lastname: Boselli
authors.forename: Chiara
authors.initials: C
authors.lastname: Catania
authors.forename: Giovanni
authors.initials: G
authors.lastname: Donadoni
authors.forename: Gilda
authors.initials: G
authors.lastname: Rossoni
authors.forename: Domenico
authors.initials: D
authors.lastname: Ghio
authors.forename: Gianluca
authors.initials: G
authors.lastname: Spitaleri
authors.forename: Cristina
authors.initials: C
authors.lastname: Ammannati
authors.forename: Scialini
authors.initials: S
authors.lastname: Colombi
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: Antonio
authors.initials: A
authors.lastname: Lambiase
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C464839:tumor necrosis factor-alpha, CNGRC fusion protein, human; D002945:Cisplatin