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.

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 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.

CONCLUSION:

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: 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
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 46 Issue 1 Pg. 198-206 (Jan 2010) ISSN: 1879-0852 [Electronic] England
• PMID: 19900802 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Biomarkers, Tumor
• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha
• tumor necrosis factor-alpha, CNGRC fusion protein, human

Topics

• Adult
• Aged
• Angiogenesis Inhibitors (administration & dosage, adverse effects, blood)
• Antineoplastic Agents (administration & dosage, adverse effects, blood)
• Biomarkers, Tumor (blood)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Neoplasms (blood, drug therapy)
• Recombinant Fusion Proteins (administration & dosage, adverse effects, blood)
• Treatment Outcome
• Tumor Necrosis Factor-alpha (administration & dosage, adverse effects, blood)