临床试验
医学
癌症
人口
临床药理学
重症监护医学
肿瘤科
药理学
内科学
环境卫生
作者
Prathap Nagaraja Shastri,Nirav N. Shah,Martin Lechmann,Hardik Mody,Marc W. Retter,Min Zhu,Tommy Li,Jun Wang,M. Naveed Shaik,Xirong Zheng,Meric Ovacik,Fei Hua,Vibha Jawa,Christophe Boetsch,Yanguang Cao,John M. Burke,Kaushik Datta,Kapil Gadkar,Vijay Upreti,Alison Betts
摘要
T‐cell‐engaging bispecific antibodies (TCEs) that target tumor antigens and T cells have shown great promise in treating cancer, particularly in hematological indications. The clinical development of TCEs often involves a lengthy first‐in‐human (FIH) trial with many dose‐escalation cohorts leading up to an early proof of concept (POC), enabling either a no‐go decision or dose selection for further clinical development. Multiple factors related to the target, product, disease, and patient population influence the efficacy and safety of TCEs. The intricate mechanism of action limits the translatability of preclinical models to the clinic, thereby posing challenges to streamline clinical development. In addition, unlike traditional chemotherapy, the top dose and recommended phase II doses (RP2Ds) for TCEs in the clinic are often not guided by the maximum tolerated dose (MTD), but rather based on the integrated dose–response assessment of the benefit/risk profile. These uncertainties pose complex challenges for translational and clinical pharmacologists (PK/PD scientists), as well as clinicians, to design an efficient clinical study that guides development. To that end, experts in the field, under the umbrella of the American Association of Pharmaceutical Scientists, have reviewed learnings from published literature and currently marketed products to share perspectives on the FIH and clinical pharmacology strategies to support early clinical development of TCEs.
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