Phase I study of NGR-hTNF, a selective vascular targeting agent, in combination with cisplatin in refractory solid tumors

Vanesa Gregorc, Filippo G. De Braud, Tommaso M. De Pas, Roberto Scalamogna, Giovanni Citterio, Alessandra Milani, Sabrina Boselli, Chiara Catania, Giovanni Donadoni, Gilda Rossoni, Domenico Ghio, Gianluca Spitaleri, Cristina Ammannati, Scialini Colombi, Federico Caligaris-Cappio, Antonio Lambiase, Claudio Bordignon

Research output: Contribution to journalArticlepeer-review


Purpose: 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. Experimental Design: 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.

Original languageEnglish
Pages (from-to)1964-1972
Number of pages9
JournalClinical Cancer Research
Issue number7
Publication statusPublished - Apr 1 2011

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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