Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics
Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics
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DOI：
10.1200/jco.2008.21.0807
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发表时间：
2009-09-01
影响因子：
45.3
通讯作者：
Bruno, Rene
中科院分区：
文献类型：
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作者：
Claret, Laurent;Girard, Pascal;Bruno, Rene
目的我们开发了一个药物-疾病模拟模型，用于根据II期临床试验中纵向肿瘤大小数据预测III期研究中的抗肿瘤反应和总生存期。使用卡培他滨的II期数据（n = 34）和氟尿嘧啶的历史III期数据（FU; n = 252）在结直肠癌（CRC）中;我们开发了一个参数生存模型，使用历史III期数据（n = 245）将肿瘤大小和患者特征的变化与生存时间联系起来。该模型进行了验证，在一个独立的III期研究（n = 1,000重复）卡培他滨与FU在CRC.ResultsThe TGI模型提供了一个很好的拟合纵向肿瘤大小数据的抗肿瘤反应和生存的模拟。对数正态分布最能描述生存时间，基线肿瘤大小和第7周肿瘤大小较基线的变化是预测因素（P < .00001）。III期研究中卡培他滨和FU的肿瘤大小和生存时间分布的预测变化与观察值一致，例如，431天（90%预测区间，362至514天），而卡培他滨组观察到的生存期为401天。（90%的预测区间，-21至110天）与35天观察到的预测capecitabine.ConclusionThe建模框架成功地预测生存期的基础上，卡培他滨第二阶段的数据在CRC的III期试验。它是支持II期结束决定和III期研究设计的有用工具。
PurposeWe developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials.MethodsWe developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC.ResultsThe TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, -21 to 110 days) versus 35 days observed was predicted for capecitabine.ConclusionThe modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies.