Université de Paris, INSERM, IAME, F-75006 Paris, France.
Merck Institute for Pharmacometrics, Merck Serono S.A, Lausanne, Switzerland.
CPT Pharmacometrics Syst Pharmacol. 2020 Dec;9(12):686-694. doi: 10.1002/psp4.12564. Epub 2020 Nov 5.
There is still a lack of efficient designs for identifying the dose response in oncology combination therapies in early clinical trials. The concentration response relationship can be identified using the early tumor shrinkage time course, which has been shown to be a good early response marker of clinical efficacy. The performance of various designs using an exposure-tumor growth inhibition model was explored using simulations. Different combination effects of new drug M and cetuximab (reference therapy) were explored first assuming no effect of M on cetuximab (to investigate the type I error (α)), and subsequently assuming additivity or synergy between cetuximab and M. One-arm, two-arm, and four-arm designs were evaluated. In the one-arm design, 60 patients received cetuximab + M. In the two-arm design, 30 patients received cetuximab and 30 received cetuximab + M. In the four-arm design, in addition to cetuximab and cetuximab + M as standard doses, combination arms with lower doses of cetuximab were evaluated (15 patients/arm). Model-based predictions or "simulated observations" of early tumor shrinkage at week 8 (ETS8) were compared between the different arms. With the same number of individuals, the one-arm design showed better statistical power than other designs but led to strong inflation of α in case of misestimated reference for ETS8 value. The two-arm design protected against this misestimation and, with the same total number of subjects, would provide higher statistical power than a four-arm design. However, a four-arm design would be helpful for exploring more doses of cetuximab in combination with M to better understand the interaction.
在早期临床试验中，确定肿瘤联合治疗的剂量反应仍然缺乏有效的设计。通过早期肿瘤退缩时间过程可以确定浓度反应关系，这已被证明是临床疗效的良好早期反应标志物。通过模拟，探讨了使用暴露-肿瘤生长抑制模型的各种设计的性能。首先假设新药 M 对西妥昔单抗没有影响（研究 I 型错误 (α)），然后假设西妥昔单抗和 M 之间具有相加或协同作用，探索了各种新的药物 M 和西妥昔单抗（参考治疗）的组合效果。评估了单臂、双臂和四臂设计。在单臂设计中，60 名患者接受西妥昔单抗+M 治疗。在双臂设计中，30 名患者接受西妥昔单抗，30 名患者接受西妥昔单抗+M。在四臂设计中，除了西妥昔单抗和西妥昔单抗+M 的标准剂量外，还评估了西妥昔单抗低剂量的组合臂（每臂 15 名患者）。比较了不同臂之间第 8 周（ETS8）早期肿瘤退缩的基于模型的预测或“模拟观察”。在相同数量的个体中，单臂设计比其他设计具有更好的统计功效，但如果 ETS8 值的参考值估计错误，会导致 α 的强烈膨胀。双臂设计可以防止这种错误估计，并且在相同的受试者总数下，与四臂设计相比，提供更高的统计功效。然而，四臂设计有助于探索与 M 联合使用更多剂量的西妥昔单抗，以更好地了解相互作用。
