Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
J Clin Oncol. 2023 Jun 20;41(18):3408-3422. doi: 10.1200/JCO.22.02430. Epub 2023 Apr 4.
There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders.
After a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved.
Combinations of anticancer therapies should be developed on the basis of mechanism of action and robust preclinical evaluation, and may include data from adult clinical trials. The general principle for combination early-phase studies is that, when possible, clinical trials should be dose- and schedule-confirmatory rather than dose-exploratory, and every effort should be made to optimize doses early. Efficient early-phase combination trials should be seamless, including dose confirmation and randomized expansion. Dose evaluation designs for combinations depend on the extent of previous knowledge. If not previously evaluated, limited evaluation of monotherapy should be included in the same clinical trial as the combination. Randomized evaluation of a new agent plus standard therapy versus standard therapy is the most effective approach to isolate the effect and toxicity of the novel agent. Platform trials may be valuable in the evaluation of combination studies. Patient advocates and regulators should be engaged with investigators early in a proposed clinical development pathway and trial design must consider regulatory requirements.
An optimized, agreed approach to the design and evaluation of early-phase pediatric combination trials will accelerate drug development and benefit all stakeholders, most importantly children and adolescents with cancer.
越来越需要使用联合策略来评估儿童癌症的创新药物。强有力的生物学原理和临床经验表明，对于大多数疾病来说，多种药物比单一药物更有效，并且可能克服耐药机制并增加协同作用。评估这些联合试验的过程需要最大限度地提高效率，并且应该得到所有利益相关者的认可。
在审查了现有的联合试验方法学、监管要求和当前结果之后，利益相关者之间达成了共识。
抗癌疗法的组合应基于作用机制和强大的临床前评估进行开发，并且可以包括来自成人临床试验的数据。联合早期研究的一般原则是，在可能的情况下，临床试验应该是剂量和方案确认性的，而不是剂量探索性的，并且应该尽一切努力尽早优化剂量。高效的早期联合试验应该是无缝的，包括剂量确认和随机扩展。组合的剂量评估设计取决于先前知识的程度。如果以前未进行评估，则应在同一临床试验中对单药治疗进行有限评估。新药物加标准疗法与标准疗法的随机评估是分离新型药物的效果和毒性的最有效方法。平台试验可能对组合研究的评估具有价值。患者权益倡导者和监管机构应尽早参与拟议的临床开发途径和试验设计，并且必须考虑监管要求。
优化、一致的早期儿科联合试验设计和评估方法将加速药物开发并使所有利益相关者受益，尤其是患有癌症的儿童和青少年。
