Optimizing natural killer cell doses for heterogeneous cancer patients on the basis of multiple event times
Optimizing natural killer cell doses for heterogeneous cancer patients on the basis of multiple event times
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DOI：
10.1111/rssc.12271
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发表时间：
2019-02-01
影响因子：
1.6
通讯作者：
Rezvani, Katy
中科院分区：
文献类型：
--
作者：
Lee, Juhee;Thall, Peter F.;Rezvani, Katy
提出了一种序贯自适应贝叶斯设计，用于脐带血来源的自然杀伤细胞治疗严重血液系统恶性肿瘤的临床试验。给出由疾病类型和严重程度定义的六个预后亚组，目标是优化每个亚组的细胞剂量。该试验有五个共同的主要结果：严重毒性的时间，细胞因子释放综合征，疾病进展或反应和死亡。该设计假设了一个多变量的威布尔回归模型，边际取决于剂量、亚组和患者的脆弱程度，这些因素导致了事件时间之间的关联。得出细胞输注后前100天内所有可能的非致命性结果组合的效用，并以后验平均效用作为优化剂量的标准。对于每个亚组，设计停止累积具有不可接受的高死亡率的剂量，并在试验结束时选择最佳安全剂量。为了验证设计的安全性、确定最佳剂量的能力和稳健性，并将其与忽略患者异质性的简化设计进行比较，提出了一项模拟研究。
A sequentially adaptive Bayesian design is presented for a clinical trial of cord-blood-derived natural killer cells to treat severe haematologic malignancies. Given six prognostic subgroups defined by disease type and severity, the goal is to optimize cell dose in each subgroup. The trial has five co-primary outcomes: the times to severe toxicity, cytokine release syndrome, disease progression or response and death. The design assumes a multivariate Weibull regression model, with marginals depending on dose, subgroup and patient frailties that induce association between the event times. Utilities of all possible combinations of the non-fatal outcomes over the first 100 days following cell infusion are elicited, with posterior mean utility used as a criterion to optimize the dose. For each subgroup, the design stops accrual to doses having an unacceptably high death rate and at the end of the trial selects the optimal safe dose. A simulation study is presented to validate the design's safety, ability to identify optimal doses and robustness, and to compare it with a simplified design that ignores patient heterogeneity.