Phase I and pharmacodynamic study of high-dose NGR-hTNF in patients with refractory solid tumours.

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 (K(trans)) 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 C(max) (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 K(trans) values (P<0.0001), which inversely correlated with NGR-hTNF C(max) (P=0.03) and baseline K(trans) values (P<0.0001). Lower sTNF-R2 levels and greater K(trans) 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.

• Authors: P A Zucali, M Simonelli, F De Vincenzo, E Lorenzi, M Perrino, M Bertossi, R Finotto, S Naimo, L Balzarini, C Bonifacio, I Timofeeva, G Rossoni, G Mazzola, A Lambiase, C Bordignon, A Santoro
• Journal: British journal of cancer (Br J Cancer) Vol. 108 Issue 1 Pg. 58-63 (Jan 15 2013) ISSN: 1532-1827 [Electronic] England
• PMID: 23169299 (Publication Type: Clinical Trial, Journal Article)

Chemical References

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

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Recombinant Fusion Proteins (administration & dosage, adverse effects)
• Tumor Necrosis Factor-alpha (administration & dosage, adverse effects)
• Young Adult