Department of Oncology, Humanitas Cancer Center IRCCS, Rozzano, Italy.
Br J Cancer. 2013 Jan 15;108(1):58-63. doi: 10.1038/bjc.2012.506. Epub 2012 Nov 20.
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).
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.
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.
asparagine-glycine-arginine-hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects.
NGR-hTNF 利用肽天冬酰胺-甘氨酸-精氨酸（NGR）选择性地将肿瘤坏死因子（TNF）靶向到 CD13 过表达的肿瘤血管。先前已确定 NGR-hTNF 的最大耐受剂量（MTD）为 45μg/m²，作为 1 小时输注，剂量限制性毒性为 3 级输注相关反应。我们通过降低输注速度（2 小时）和使用预用药（扑热息痛）进一步探索了剂量递增。
每个剂量水平（n=48；60-325μg/m²）各有 4 名患者入组。治疗前后评估药代动力学、可溶性 TNF 受体（sTNF-R1/sTNF-R2）和通过动态成像（动态对比增强磁共振成像（DCE-MRI））测量的容积转移常数（K(trans)）。
常见的相关毒性包括 1/2 级寒战（58%）。未达到最大耐受剂量。C(max)（P<0.0001）和血浆浓度-时间曲线下面积（P=0.0001）均与剂量成比例增加。治疗后 sTNF-R2 水平显著高于 sTNF-R1（P<0.0001）。然而，sTNF-Rs 的变化在不同剂量水平之间没有差异，表明在脱落动力学方面存在平台效应。作为最佳反应，41 名可评估患者中有 12 名（29%）疾病稳定。通过 DCE-MRI，37 名评估患者中有 28 名（76%）治疗后 K(trans)值降低（P<0.0001），与 NGR-hTNF C(max)（P=0.03）和基线 K(trans)值（P<0.0001）呈负相关。第一个周期后 sTNF-R2 水平较低和 K(trans)降低较多与改善生存相关。
天冬酰胺-甘氨酸-精氨酸-hTNF 可以安全地在高于 MTD 的剂量递增，诱导低受体脱落和早期抗血管作用。
