Berdel Wolfgang E, Harrach Saliha, Brand Caroline, Brömmel Kathrin, Berdel Andrew F, Hintelmann Heike, Schliemann Christoph, Schwöppe Christian
Department of Medicine A Hematology and Oncology, University Hospital Muenster, D-48149 Muenster, Germany.
Cancers (Basel). 2020 Nov 26;12(12):3536. doi: 10.3390/cancers12123536.
CD-13 targeted tissue factor tTF-NGR is a fusion protein selectively inducing occlusion of tumor vasculature with resulting tumor infarction. Mechanistic and pharmacodynamic studies have shown broad anti-tumor therapeutic effects in xenograft models.
After successful Good Manufacturing Practice (GMP) production and before translation into clinical phase I, ICH S9 (S6) guideline-conforming animal safety, toxicology, and pharmacokinetic (PK) studies were requested by the federal drug authority in accordance with European and US regulations.
These studies were performed in mice, rats, guinea pigs, and beagle dogs. Results of the recently completed clinical phase I trial in end-stage cancer patients showed only limited predictive value of these non-clinical studies for patient tolerability and safety in phase I.
Although this experience cannot be generalized, alternative pathways with seamless clinical phase 0 microdosing-phase I dose escalation studies are endorsed for anticancer drug development and translation into the clinic.
靶向CD - 13的组织因子tTF - NGR是一种融合蛋白，可选择性诱导肿瘤血管闭塞，导致肿瘤梗死。机制和药效学研究已在异种移植模型中显示出广泛的抗肿瘤治疗效果。
在成功进行药品生产质量管理规范（GMP）生产后，且在转入临床I期之前，联邦药物管理机构根据欧洲和美国法规要求进行符合国际人用药品注册技术协调会S9（S6）指南的动物安全性、毒理学和药代动力学（PK）研究。
这些研究在小鼠、大鼠、豚鼠和比格犬中进行。最近完成的终末期癌症患者临床I期试验结果表明，这些非临床研究对I期患者耐受性和安全性的预测价值有限。
尽管这一经验不能一概而论，但支持采用无缝临床0期微剂量给药 - I期剂量递增研究的替代途径进行抗癌药物研发并转化至临床应用。
