Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours

Vanesa Gregorc, Giovanni Citterio, Giordano Vitali, Anna Spreafico, Paola Scifo, Anna Borri, Giovanni Donadoni, Gilda Rossoni, Angelo Corti, Federico Caligaris-Cappio, Alessandro Del Maschio, Antonio Esposito, Francesco De Cobelli, Flavio Dell'Acqua, Antonella Troysi, Paolo Bruzzi, Antonio Lambiase, Claudio Bordignon

Research output: Contribution to journalArticle

Abstract

Background: NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-α) 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. Patients and 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 μg/m2). 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 μg/m2 had a grade 3 drug-related toxicity (chills and dyspnoea). Both Cmax and AUC increased proportionally with dose. No shedding of soluble TNF-α receptors was observed up to 0.8 μg/m2. Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of Ktrans, which was more pronounced at 0.8 μg/m2. 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. Conclusion: Based on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 μg/m2 will be further developed either as single-agent or with standard chemotherapy.

Original languageEnglish
Pages (from-to)198-206
Number of pages9
JournalEuropean Journal of Cancer
Volume46
Issue number1
DOIs
Publication statusPublished - Jan 2010

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Blood Vessels
Neoplasms
Chills
Tumor Necrosis Factor Receptors
NGR peptide
Magnetic Resonance Imaging
Vascular Tissue Neoplasms
CD13 Antigens
Drug-Related Side Effects and Adverse Reactions
Vascular Diseases
Dyspnea
Colonic Neoplasms
Area Under Curve
tumor necrosis factor-alpha, CNGRC fusion protein, human
Protein Isoforms
Endothelial Cells
Pharmacokinetics
Tumor Necrosis Factor-alpha
Biomarkers
Ligands

Keywords

  • NGR-hTNF
  • Phase I
  • Solid tumours

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gregorc, V., Citterio, G., Vitali, G., Spreafico, A., Scifo, P., Borri, A., ... Bordignon, C. (2010). Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours. European Journal of Cancer, 46(1), 198-206. https://doi.org/10.1016/j.ejca.2009.10.005

Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours. / Gregorc, Vanesa; Citterio, Giovanni; Vitali, Giordano; Spreafico, Anna; Scifo, Paola; Borri, Anna; Donadoni, Giovanni; Rossoni, Gilda; Corti, Angelo; Caligaris-Cappio, Federico; Maschio, Alessandro Del; Esposito, Antonio; De Cobelli, Francesco; Dell'Acqua, Flavio; Troysi, Antonella; Bruzzi, Paolo; Lambiase, Antonio; Bordignon, Claudio.

In: European Journal of Cancer, Vol. 46, No. 1, 01.2010, p. 198-206.

Research output: Contribution to journalArticle

Gregorc, V, Citterio, G, Vitali, G, Spreafico, A, Scifo, P, Borri, A, Donadoni, G, Rossoni, G, Corti, A, Caligaris-Cappio, F, Maschio, AD, Esposito, A, De Cobelli, F, Dell'Acqua, F, Troysi, A, Bruzzi, P, Lambiase, A & Bordignon, C 2010, 'Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours', European Journal of Cancer, vol. 46, no. 1, pp. 198-206. https://doi.org/10.1016/j.ejca.2009.10.005
Gregorc, Vanesa ; Citterio, Giovanni ; Vitali, Giordano ; Spreafico, Anna ; Scifo, Paola ; Borri, Anna ; Donadoni, Giovanni ; Rossoni, Gilda ; Corti, Angelo ; Caligaris-Cappio, Federico ; Maschio, Alessandro Del ; Esposito, Antonio ; De Cobelli, Francesco ; Dell'Acqua, Flavio ; Troysi, Antonella ; Bruzzi, Paolo ; Lambiase, Antonio ; Bordignon, Claudio. / Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours. In: European Journal of Cancer. 2010 ; Vol. 46, No. 1. pp. 198-206.
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AU - Citterio, Giovanni

AU - Vitali, Giordano

AU - Spreafico, Anna

AU - Scifo, Paola

AU - Borri, Anna

AU - Donadoni, Giovanni

AU - Rossoni, Gilda

AU - Corti, Angelo

AU - Caligaris-Cappio, Federico

AU - Maschio, Alessandro Del

AU - Esposito, Antonio

AU - De Cobelli, Francesco

AU - Dell'Acqua, Flavio

AU - Troysi, Antonella

AU - Bruzzi, Paolo

AU - Lambiase, Antonio

AU - Bordignon, Claudio

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N2 - Background: NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-α) 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. Patients and 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 μg/m2). 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 μg/m2 had a grade 3 drug-related toxicity (chills and dyspnoea). Both Cmax and AUC increased proportionally with dose. No shedding of soluble TNF-α receptors was observed up to 0.8 μg/m2. Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of Ktrans, which was more pronounced at 0.8 μg/m2. 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. Conclusion: Based on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 μg/m2 will be further developed either as single-agent or with standard chemotherapy.

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