Department of Oncology, Istituto Scientifico San Raffaele, Milan, Italy.
Eur J Cancer. 2010 Jan;46(1):198-206. doi: 10.1016/j.ejca.2009.10.005.
NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-alpha) fused to the tumour-homing peptide NGR, a ligand of an aminopeptidase N/CD13 isoform, which is overexpressed on endothelial cells of newly formed tumour blood vessels. NGR-TNF showed a biphasic dose-response curve in preclinical models. This study exploring the low-dose range aimed to define safety and optimal biological dose of NGR-hTNF.
Pharmacokinetics, plasma biomarkers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated at baseline and after each cycle in 16 patients enrolled at four doubling-dose levels (0.2-0.4-0.8-1.6 microg/m(2)). NGR-hTNF was given intravenously as 1-h infusion every 3 weeks (q3w). Tumour response was assessed q6w.
Eighty-three cycles (median, 2; range, 1-29) were administered. Most frequent treatment-related toxicity was grade 1-2 chills (69%), occurring during the first infusions. Only one patient treated at 1.6 microg/m(2) had a grade 3 drug-related toxicity (chills and dyspnoea). Both C(max) and AUC increased proportionally with dose. No shedding of soluble TNF-alpha receptors was observed up to 0.8 microg/m(2). Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of K(trans), which was more pronounced at 0.8 microg/m(2). Seven patients (44%) had stable disease for a median time of 5.9 months, including a colon cancer patient who experienced an 18-month progression-free time.
Based on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 microg/m(2) will be further developed either as single-agent or with standard chemotherapy.
NGR-hTNF 由人肿瘤坏死因子-α（hTNF-α）与肿瘤归巢肽 NGR 融合而成，NGR 是一种氨肽酶 N/CD13 同工型的配体，在新形成的肿瘤血管内皮细胞上过度表达。NGR-TNF 在临床前模型中表现出双相剂量反应曲线。本研究旨在探索低剂量范围，以确定 NGR-hTNF 的安全性和最佳生物学剂量。
在 16 名患者的四个加倍剂量水平（0.2-0.4-0.8-1.6μg/m²）中，在基线和每个周期后评估药代动力学、血浆生物标志物和动态对比增强磁共振成像（DCE-MRI）。NGR-hTNF 作为每 3 周一次的 1 小时静脉输注（q3w）给予。每 6 周评估一次肿瘤反应。
共给予 83 个周期（中位数为 2；范围为 1-29）。最常见的与治疗相关的毒性是 1-2 级寒战（69%），发生在第一次输注期间。只有一名接受 1.6μg/m² 治疗的患者出现 3 级与药物相关的毒性（寒战和呼吸困难）。Cmax 和 AUC 均随剂量成比例增加。在 0.8μg/m² 时，未观察到可溶性 TNF-α 受体的脱落。75%的 DCE-MRI 评估患者显示 Ktrans 随时间下降，在 0.8μg/m² 时更为明显。7 名患者（44%）有稳定的疾病，中位时间为 5.9 个月，包括一名结肠癌患者，其无进展时间为 18 个月。
基于耐受性、可溶性 TNF 受体动力学、抗血管作用和疾病控制，NGR-hTNF 0.8μg/m² 将进一步开发为单一药物或与标准化疗联合使用。
