A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma.
A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma.
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DOI：
10.1158/1078-0432.ccr-22-1169
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发表时间：
2022-09-15
影响因子：
11.5
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
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作者：
Saulnier-Sholler, Giselle;Duda, Dan G.;Bergendahl, Genevieve;Ebb, David;Snuderl, Matija;Laetsch, Theodore W.;Michlitsch, Jennifer;Hanson, Derek;Isakoff, Michael S.;Bielamowicz, Kevin;Kraveka, Jacqueline M.;Ferguson, William;Carmeliet, Peter;De Deene, A.;Gijsen, Lore;Jain, Rakesh K.
胎盘生长因子(PlGF)及其受体NRP-1在恶性胚胎性肿瘤中升高，并通过促进细胞增殖、存活和转移而介导肿瘤进展。TB-403是一种封闭的抗PlGF的单抗，在原位髓母细胞瘤(MB)模型中可以抑制肿瘤生长并提高存活率。我们在患有复发或难治性癌症的儿科受试者中进行了TB-403的1期、开放标记、多中心、剂量递增研究。研究包括4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。受试者每周期接受2剂TB-403(第1天和第15天)。第一周期后，可加入替莫唑胺或依托泊苷。主要目标是确定TB-403单一疗法在剂量限制毒性(DLT)评估期内的最大耐受剂量(MTD)。第二和探索性目标包括疗效、药物药代动力学(PK)和药效学生物标志物的检测。15名受试者接受了4个剂量水平的治疗。所有受试者在第1周期中接受了2剂TB-403治疗。3例受试者报告了5个严重的治疗紧急不良事件，但未达到MTD。虽然没有观察到完全或部分反应，但11名复发的MB患者中有7名患者病情稳定，其中4名患者持续了100天以上。TB-403在所有剂量水平下都是安全和耐受性良好的。未达到MTD。结果看起来令人鼓舞，因此有必要进一步评估儿童MB受试者的疗效。以前对髓母细胞瘤的治疗策略已显示出适度改善的反应。然而，长期的总体生存情况仍然令人失望，许多幸存者都有深刻的长期并发症。因此，迫切需要开发新的、改进的和更安全的髓母细胞瘤治疗策略。PlGF/Nrp1通路介导的重要的肿瘤-间质相互作用使其成为一个有吸引力的靶点。我们报告了儿科受试者中抗PlGF抗体TB-403的I期、开放标记、多中心、剂量递增研究。TB403治疗耐受性好，在高危、高度预治疗的复发性髓母细胞瘤中诱导出稳定的疾病，允许极好的生活质量。这些发现表明，TB-403治疗可能是治疗儿童髓母细胞瘤的一种潜在的变革性疗法，应该在更大的研究中进行测试。
Placental growth factor (PlGF) and its receptor neuropilin 1 (NRP-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 (MB) models. We conducted a phase 1, open-label, multicenter, dose-escalation study of TB-403 in pediatric subjects with relapsed or refractory cancers. The study involved 4 dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3+3 dose-escalation scheme. Subjects received 2 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 (DLT) assessment period. The secondary and exploratory objectives included efficacy, drug pharmacokinetics (PK) and detection of pharmacodynamic biomarkers. Fifteen subjects were treated in 4 dose levels. All subjects received 2 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 MB subjects experienced stable disease, which persisted for more than 100 days in 4 out of 7 subjects. 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 MB. Previous treatment strategies for medulloblastoma have shown moderate improvement in response. However, the long-term overall survival remains disappointing, and many survivors have profound long-term complications. Therefore, there is a tremendous need to develop novel, improved and safer therapeutic strategies for medulloblastoma. The critical tumor-stroma interactions mediated by the PlGF/NRP1 pathway make it an attractive target. We report a phase I, open-label, multicenter, dose-escalation study of the anti-PlGF antibody, TB-403, in pediatric subjects. TB403 treatment was well tolerated and induced stable disease in high risk, heavily pretreated relapsed medulloblastoma allowing for excellent quality of life. These findings indicate that treatment with TB-403 may represent a potentially transformative therapy for children with medulloblastoma and should be tested in larger studies.