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

• Published in: European journal of cancer (1990) Vol. 46; no. 1; pp. 198 - 206
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.01.2010; Elsevier
• Subjects: Adult; Aged; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - adverse effects; Angiogenesis Inhibitors - blood; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - blood; Biological and medical sciences; Biomarkers, Tumor - blood; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hematology, Oncology and Palliative Medicine; Humans; Magnetic Resonance Imaging; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - blood; Neoplasms - drug therapy; NGR-hTNF; Pharmacology. Drug treatments; Phase I; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - blood; Solid tumours; Treatment Outcome; Tumor Necrosis Factor-alpha - administration & dosage; Tumor Necrosis Factor-alpha - adverse effects; Tumor Necrosis Factor-alpha - blood; Tumors; Solid tumours; NGR-hTNF; Phase I; Solid tumor; Cancerology; Targeting; Blood vessel; Advanced stage; Circulatory system; Malignant tumor; Dose; Cancer
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2009.10.005

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.