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- Title
Phase I and pharmacodynamic study of high-dose NGR-hTNF in patients with refractory solid tumours.
- Authors
Zucali, P A; Simonelli, M; De Vincenzo, F; Lorenzi, E; Perrino, M; Bertossi, M; Finotto, R; Naimo, S; Balzarini, L; Bonifacio, C; Timofeeva, I; Rossoni, G; Mazzola, G; Lambiase, A; Bordignon, C; Santoro, A
- Abstract
Background:NGR-hTNF exploits the peptide asparagine-glycine-arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR-hTNF was previously established at 45 μg m−2 as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol).Methods:Four patients entered each of 12 dose levels (n=48; 60-325 μg m−2). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (Ktrans) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre- and post-treatment.Results:Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both Cmax (P<0.0001) and area under the plasma concentration-time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment Ktrans values (P<0.0001), which inversely correlated with NGR-hTNF Cmax (P=0.03) and baseline Ktrans values (P<0.0001). Lower sTNF-R2 levels and greater Ktrans decreases after first cycle were associated with improved survival.Conclusion:asparagine-glycine-arginine-hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects.
- Subjects
PHARMACODYNAMICS; TUMOR necrosis factors; CONTRAST-enhanced magnetic resonance imaging; PREMEDICATION; ACETAMINOPHEN; ASPARAGINE; GLYCINE; ARGININE; CD134 antigen; IMAGING of cancer
- Publication
British Journal of Cancer, 2013, Vol 108, Issue 1, p58
- ISSN
0007-0920
- Publication type
Article
- DOI
10.1038/bjc.2012.506