Details

Autor(en) / Beteiligte

• Zucali, Paolo Andrea
• Simonelli, Matteo
• De Vincenzo, Fabio
• Lorenzi, Elena
• Perrino, Matteo
• Bertossi, Monica
• Balzarini, Luca
• Bonifacio, Cristina
• Lambiase, Antonio
• Bordignon, Claudio
• Santoro, Armando

Titel

Phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) trial of NGR-hTNF given at high doses in patients with refractory solid tumors

Ist Teil von

• Journal of clinical oncology, 2012-05, Vol.30 (15_suppl), p.2580-2580

Erscheinungsjahr

2012

Quelle

Elektronische Zeitschriftenbibliothek - Freely accessible e-journals

Beschreibungen/Notizen

• Abstract only 2580 Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR) peptide for selectively targeting tumor necrosis factor (TNF) to a CD13 overexpressed by tumor vasculature. Maximum tolerated dose (MTD) of NGR-hTNF was previously established at 45 µg/m 2 , when given as 1-h infusion every 3 weeks (q3w), with dose limiting toxicities (DLT) being grade 3 infusion-related reactions (IRRs). We explored further dose escalation by prolonging infusion time (2-h) and using premedication (paracetamol). Methods: DLTs were defined as drug-related grade 3/4 adverse events (AEs). PK and soluble TNF receptors (sR1-sR2) were tested in 46 pts. The volume transfer coefficient (K trans ) and initial area under gadolinium concentration (IAUGC) were assessed before and 2 hours after dosing by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in 37 pts. Results: 12 dose levels (DLs) from 60 to 325 μg/m² q3w were evaluated. 48 pts (PS 0/1: 21/27; M/F: 37/11; median age: 61 years) received a total of 117 cycles (range 1-6). Prior regimens ranged from 1 to 7 (median 3). No DLT occurred and MTD was not reached. Study-emergent grade 3 and 4 AEs were reported in 12 (25%) and 5 (10%) pts, respectively. Grade 1/2 IRRs included chills (58%) and pyrexia (56%). Both C max (p<.0001) and AUC (p=.0001) increased with dose. Post-treatment peaks of sR2 were higher than sR1 (9.6 v 4.9 ng/mL; p<.0001). However, changes in sRs did not differ across DLs, with a plateau in shedding kinetics. By DCE-MRI assessment, median pre- and post-first cycle values declined from 0.15 to 0.09 min -1 for K trans (p=.02) and from 10.2 to 7.2 mM/L/sec for IAUGC (p =.0005). Over treatment, 28 pts (76%) showed decreases in IAUGC (-47%, p<.0001) and K trans (-59%; p<.0001) that were inversely correlated with baseline K trans values (p<.0001) and NGR-hTNF C max (p=.03). Of 41 evaluable pts, 12 (29%) had stable disease for a median time of 2.9 months. Survival at 1 year was 34%, with improved survival observed in pts with lower sTNF-R2 levels (p=.01) and greater K trans reductions (p=.05) after 1st cycle. Conclusions: NGR-hTNF can be safely escalated at doses higher than MTD and induces low shedding of receptors and early antivascular effects.