In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. e22145-e22145
Abstract:
e22145 Background: Dose-response curve of NGR-hTNF, a selective antivascular agent, is typically biphasic with activity shown either at low dose (LD) or high dose (HD). Receptor shedding may block drug activity. Vascular effects at LD are characterized by early vessel stabilization and late vessel damage, while at HD by rapid vessel disruption. Methods: 60 pts (median age: 61; M/F: 44/16; PS 0/≥1: 25/35; median prior lines: 3) received in 2 ph I trials NGR-hTNF at LD (0.2-1.6 µg/m 2 ; n=14) or HD (60-325 µg/m 2 ; n=46) every 3 weeks. We tested the impact of early changes (post 1st dose) in baseline-normalized plasma receptor levels (n=60) and in DCE-MRI-assessed K trans (n=49) on treatment effect, including disease control (DC, rate of pts progression free at 6 weeks by RECIST criteria) and progression free survival (PFS). Results: Baseline receptor levels were not related to outcome. Post-dosing levels of sR1 (median, 4.6 ng/mL; interquartile range, 2.8-5.7) and sR2 (8.6; 4.5-10.7) increased with dose (p 〈 .0001 for both), with median values of sR1 (0.3) and sR2 (0.5) at LD being significantly lower than those of sR1 (4.9) and sR2 (9.6) at HD (p 〈 .0001 for both). Using as cutoff the 1st quartile, low sR1 levels (≤2.8 ng/mL) correlated with improved DC (OR=4.9; p=0.01) and PFS (HR=0.30; p=.003). In low vs high groups, median DC duration was 7.4 vs 2.9 months and 6-month PFS was 29% vs 0%, respectively. By adjusting for baseline covariates (age, sex, PS and prior lines), low sR1 levels remained independently associated with better DC (p=.02) and PFS (p=.008). Similar effects were noted for sR2. Levels of sR1 (r=-0.35; p=.01) and sR2 (r=-0.27; p=.07) inversely correlated with early fractional decreases in K trans , which resulted in median values unchanged after LD (4%; p=.73) and reduced after HD (-32%; p=.009). However, K trans significantly declined over time after both LD (-24%; p=.04) and HD (-44%; p=.001). Early changes in K trans did not relate with DC as defined by RECIST, but smaller decreases in K trans were associated with longer PFS (HR=0.56; p=.04). Conclusions: NGR-hTNF at LD is associated with better outcome than at HD likely due to early effects that involve minimal receptor shedding and vessel stabilization. Clinical trial information: NCT00878111-NCT00914628.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2013.31.15_suppl.e22145
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2013
detail.hit.zdb_id:
2005181-5
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