An Innovative Approach to Optimize First‐In‐Human Minimal Anticipated Biological Effect Level Based Starting Dose in Oncology Trials for Bispecific T‐Cell Engagers: Experience from A Solid Tumor Bispecific T‐Cell Engager

IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Clinical Pharmacology & Therapeutics Pub Date : 2024-09-17 DOI:10.1002/cpt.3431
Di Zhou, Roman Kischel, Sabine Stienen, Danielle Townsley, Alexander Sternjak, Michael Lutteropp, Julie Bailis, Matthias Friedrich, Benno Rattel, Khamir Mehta, Vijay V. Upreti
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Abstract

Bispecific T‐cell engagers (Bi‐TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best‐in‐class therapeutics for cancer. However, defining the dose and dosing regimen for the first‐in‐human (FIH) studies of Bi‐TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub‐therapeutic dosing. Leveraging our in‐depth and broad clinical development experience across three generations of Bi‐TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, in vitro, in vivo pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half‐life extended (HLE) Bi‐TCE for gastric cancer. This modified MABEL approach enabled a 10‐fold higher starting dose that was deemed safe and well tolerated and saved at least two dose‐escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi‐TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi‐TCEs.
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在双特异性 T 细胞靶向药物的肿瘤学试验中,优化基于最小预期生物效应水平的首次人体试验起始剂量的创新方法:来自实体瘤双特异性 T 细胞参与疗法的经验
双特异性 T 细胞吸引剂(Bi-TCEs)彻底改变了血液病和实体瘤的治疗和管理,有机会成为一流的癌症治疗药物。然而,为双T细胞捕获剂的首次人体(FIH)研究确定剂量和给药方案具有挑战性,因为高起始剂量会使受试者面临严重毒性,而基于传统最小预期生物效应水平(MABEL)方法的低起始剂量则可能导致漫长的剂量升级,使重症患者面临亚治疗剂量。利用我们在液体和实体瘤适应症方面三代 Bi-TCE 深入而广泛的临床开发经验,我们开发了一种创新的修正 MABEL 方法,用于起始剂量的选择,该方法综合了基于靶点生物学、适应症、毒理学、体外和体内药理学评估、转化药代动力学/药效学 (PK/PD) 模型以及预期安全性的知识。传统的 MABEL 方法通常使用较高的效应细胞与靶细胞(E:T)比例,相比之下,我们的创新方法采用了优化的 E:T 细胞比例,能更好地反映肿瘤微环境。这种改良的 MABEL 方法被成功应用于胃癌半衰期延长 (HLE) BiTCE 的 FIH 剂量选择。这种改进的 MABEL 方法使起始剂量提高了 10 倍,被认为是安全且耐受性良好的,并且在达到预计有效剂量之前至少节省了两个剂量递增队列。这种方法已成功获得全球监管机构的认可,可用于血液病和实体瘤适应症的双 TCE,以加快双 TCE 的临床开发。
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来源期刊
CiteScore
12.70
自引率
7.50%
发文量
290
审稿时长
2 months
期刊介绍: Clinical Pharmacology & Therapeutics (CPT) is the authoritative cross-disciplinary journal in experimental and clinical medicine devoted to publishing advances in the nature, action, efficacy, and evaluation of therapeutics. CPT welcomes original Articles in the emerging areas of translational, predictive and personalized medicine; new therapeutic modalities including gene and cell therapies; pharmacogenomics, proteomics and metabolomics; bioinformation and applied systems biology complementing areas of pharmacokinetics and pharmacodynamics, human investigation and clinical trials, pharmacovigilence, pharmacoepidemiology, pharmacometrics, and population pharmacology.
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