PO.ADV01 · 患者倡导
早期阶段肿瘤学试验中的回填入组:从患者视角看剂量探索创新
Backfilling in early-phase oncology trials: A patient perspective on dose-finding innovation
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
早期阶段临床试验旨在确定安全有效的给药策略,从临床和患者双重视角平衡抗肿瘤活性与可接受的毒性。以往,剂量探索研究主要侧重于确定能够安全耐受的最高剂量。然而,随着靶向疗法和免疫疗法的出现,目标日益转向确定既能维持生物学活性、又能将副作用控制在可接受范围内的剂量,即在保持副作用可接受的同时尽量减少不必要的毒性。“回填入组”(Backfilling)是指在测试更高剂量的同时,于已证实安全的较低剂量水平并行招募额外的患者。这有助于更深入地理解药物的行为、抗癌活性及其与代谢和生物学标志物的相互作用,从而更有把握地为后线试验选择最合适的剂量。重要的是,许多疗法在不同剂量范围内表现出不同的生物学效应,这意味着收集多个剂量水平的数据可能揭示出仅关注最高耐受剂量的剂量探索所无法体现的活性。近期支持剂量优化的监管举措和指南反映了这一不断演进的理念。美国食品药品监督管理局(FDA,2024)和创新癌症疗法开发方法学(MDICT)工作组(2022)均鼓励剂量探索研究考虑毒性以外的更广泛信息/证据,并强调回填入组在生成更丰富的数据集、收集额外信息以最终帮助选择最佳剂量方面的价值。从患者倡导者的视角来看,回填入组不仅仅是一项技术性的改进。它是一种切实可行的策略,能够扩大招募机会,并使更多信息在药物开发的早期得以收集。这有助于更早地确定有效且可耐受的剂量,并减少因需要额外试验来重新界定合适剂量所造成的延误。通过增进对治疗在不同剂量水平下表现的理解,回填入组可能有助于减少不必要的毒性和代谢负担。因此,将患者视角纳入试验方法学的讨论,有助于确保剂量探索策略不仅在科学上稳健,而且更好地契合耐受性和真实世界的患者体验,从而为当前和未来的患者提供更温和、更易耐受的治疗。
查看英文原文 English abstract
Early-phase clinical trials aim to identify safe andeffective dosing strategies, balancing anti-tumour activity with acceptabletoxicity from both clinical and patient perspectives. Historically,dose-finding studies have largely focused on identifying the highest dose thatcan be safely tolerated. However, with targeted therapies and immunotherapies,the goal has increasingly shifted toward identifying doses that maintainbiological activity while keeping side effects acceptable. minimisingunnecessary toxicity and keeping side effects acceptable.“Backfilling” refers to the concurrent enrolment ofadditional patients at lower dose levels, which have already shown to be safe,while a higher dose is currently tested. This enables deeper understanding ofdrug behaviour, anti-cancer activity, and interactions with metabolic andbiological markers, supporting more confident selection of the most appropriatedose for later-phase trials. Importantly, many therapies demonstrate differentbiological effects across dose ranges, meaning that collecting data acrossmultiple dose levels may reveal activity that would not be evident ifdose-finding focused only on identifying the highest tolerated dose.Recent regulatory initiatives and guidance supporting doseoptimisation reflect this evolving approach. The United States of America Foodand Drug Administration (FDA, 2024) and the Methodology for the Development ofInnovative Cancer Therapies (MDICT) Taskforce (2022) both encourage dosefinding studies to consider broader information/evidence than toxicity aloneand highlight the value of backfilling in generating richer datasets collectingadditional information that will ultimately help selecting the optimal dose.From a patient-advocate perspective, backfilling is morethan a technical refinement. It is a practical strategy that widens recruitmentopportunities and allows additional information to be gathered earlier in drugdevelopment. This can help identify effective and tolerable dosing sooner andreduce delays caused by needing additional trials to redefine the appropriatedose. By improving understanding of how treatments behave across dose levels,backfilling may help reduce unnecessary toxicity and metabolic stress.Integrating patient perspectives into trial methodology discussions cantherefore help ensure dose-finding strategies are not only scientificallyrobust but also better aligned with tolerability and real-world patientexperience, enabling kinder, better-tolerated treatments for both current andfuture patients.
利益披露 Disclosure
K. Spencer, None.