Purpose: Placental growth factor (PlGF) and its receptor neuropilin 1 are elevated in malignant embryonal tumors and mediate tumor progression by promoting cell proliferation, survival, and metastasis. TB-403 is a blocking monoclonal antibody against PlGF that inhibits tumor growth and increases survival in orthotopic medulloblastoma models. Patients and Methods: We conducted a phase I, open-label, multicenter, dose-escalation study of TB-403 in pediatric subjects with relapsed or refractory cancers. The study involved four dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3 + 3 dose-escalation scheme. Subjects received two doses of TB-403 (days 1 and 15) per cycle. After cycle 1, temozolomide or etoposide could be added. The primary objective was to determine the maximum tolerated dose (MTD) of TB-403 monotherapy during a dose-limiting toxicity assessment period. The secondary and exploratory objectives included efficacy, drug pharmacokinetics, and detection of pharmacodynamic biomarkers. Results: Fifteen subjects were treated in four dose levels. All subjects received two doses of TB-403 in cycle 1. Five serious treatment-emergent adverse events were reported in 3 subjects, but MTD was not reached. While no complete nor partial responses were observed, 7 of 11 relapsed subjects with medulloblastoma experienced stable disease, which persisted for more than 100 days in 4 of 7 subjects. Conclusions: TB-403 was safe and well tolerated at all dose levels. No MTD was reached. The results look encouraging and therefore warrant further evaluation of efficacy in pediatric subjects with medulloblastoma.

中文翻译：

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TB-403 治疗复发性髓母细胞瘤、神经母细胞瘤、尤文肉瘤和腺泡横纹肌肉瘤的 I 期试验

目的：胎盘生长因子 (PlGF) 及其受体神经毡蛋白 1 在恶性胚胎肿瘤中升高，并通过促进细胞增殖、存活和转移来介导肿瘤进展。TB-403 是一种针对 PlGF 的阻断性单克隆抗体，可抑制肿瘤生长并提高原位髓母细胞瘤模型的存活率。患者和方法：我们在患有复发性或难治性癌症的儿科受试者中进行了 TB-403 的 I 期、开放标签、多中心、剂量递增研究。该研究涉及四个剂量水平（20 mg/kg、50 mg/kg、100 mg/kg、175 mg/kg），采用 3 + 3 剂量递增方案。受试者每个周期接受两剂 TB-403（第 1 天和第 15 天）。第 1 周期后，可以添加替莫唑胺或依托泊苷。主要目的是确定剂量限制毒性评估期间 TB-403 单药治疗的最大耐受剂量 (MTD)。次要和探索性目标包括功效、药物药代动力学和药效生物标志物的检测。结果：十五名受试者接受四种剂量水平的治疗。所有受试者在第 1 周期接受两剂 TB-403。3 名受试者报告了 5 例严重的治疗引起的不良事件，但未达到 MTD。虽然没有观察到完全或部分缓解，但 11 名复发性髓母细胞瘤受试者中有 7 名病情稳定，7 名受试者中有 4 名病情持续超过 100 天。结论：TB-403 在所有剂量水平下都是安全且耐受性良好的。未达到 MTD。