Background and Objective

A phase I/II trial evaluated the safety, antitumor activity, and pharmacokinetics of avelumab (anti-PD-L1 antibody) in pediatric patients with refractory/relapsed solid tumors (NCT03451825). This study aimed to inform avelumab dose selection in pediatric populations using population pharmacokinetic modeling and simulations.

Methods

Patients aged < 18 years with refractory/relapsed solid tumors enrolled in phase I received avelumab 10 or 20 mg/kg intravenously every 2 weeks. A pediatric population pharmacokinetic model was developed via the frequentist prior approach.

Results

Pharmacokinetic parameters from 21 patients who received avelumab 10 mg/kg (n = 6) or 20 mg/kg (n = 15) were analyzed. Patients had a wide range of weights and ages (medians, 37.3 kg and 12 years). Exposures with 10-mg/kg dosing were lower vs adult dosing, particularly in patients weighing < 40 kg, whereas 20-mg/kg dosing achieved or exceeded adult exposures, irrespective of body weight. A two-compartment linear model with time-varying clearance using body weight as a covariate, with the frequentist prior approach, best described pediatric data. In this model, optimal overlap in exposure with adult data was achieved with 800 mg every 2 weeks for patients aged ≥ 12 years and weighing ≥ 40 kg, and 15 mg/kg every 2 weeks for patients aged < 12 years or weighing < 40 kg.

Conclusions

Based on exposure matching, the recommended doses for further avelumab studies, including combination studies, are 15 mg/kg every 2 weeks for pediatric patients aged < 12 years or weighing < 40 kg and the adult flat dose of 800 mg every 2 weeks for pediatric patients aged ≥ 12 years and weighing ≥ 40 kg.

Clinical Trial Registration

ClinicalTrials.gov NCT03451825.

中文翻译：

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用于实体瘤儿科患者临床研究的 Avelumab 剂量选择

背景与目的

一项 I/II 期试验评估了 avelumab（抗 PD-L1 抗体）在患有难治性/复发性实体瘤的儿科患者中的安全性、抗肿瘤活性和药代动力学（NCT03451825）。本研究旨在通过群体药代动力学建模和模拟为儿科人群中的 avelumab 剂量选择提供信息。

方法

年龄 < 18 岁的难治性/复发性实体瘤患者在 I 期入组，每 2 周接受 10 或 20 mg/kg 的 avelumab 静脉注射。儿科人群药代动力学模型是通过常客先验方法开发的。

结果

分析了 21 名接受 avelumab 10 mg/kg ( n = 6) 或 20 mg/kg ( n = 15) 的患者的药代动力学参数。患者的体重和年龄范围很广（中位数为 37.3 公斤和 12 岁）。10-mg/kg 剂量的暴露低于成人剂量，特别是在体重 < 40 kg 的患者中，而 20-mg/kg 剂量达到或超过成人暴露，与体重无关。使用体重作为协变量的具有时变清除率的两室线性模型，采用频率论先验方法，最好地描述了儿科数据。在此模型中，对于年龄 ≥ 12 岁且体重 ≥ 40 kg 的患者，每 2 周 800 mg 和 15 mg/kg 年龄 < 12 岁或体重 < 40 kg 的患者每 2 周 15 mg/kg 实现了与成人数据的最佳暴露重叠.

结论

根据暴露匹配，进一步 avelumab 研究（包括联合研究）的推荐剂量是，对于年龄 < 12 岁或体重 < 40 kg 的儿科患者，每 2 周 15 mg/kg 和对于儿科患者的成人固定剂量为每 2 周 800 mg年龄≥ 12 岁且体重≥ 40 kg 的患者。

临床试验注册

ClinicalTrials.gov NCT03451825。