Yada Shinjo, Hamada Chikuma
Faculty of Engineering, Tokyo University of Science, Tokyo, Japan.
Department of Biostatistics, A2 Healthcare Corporation, Tokyo, Japan.
Pharm Stat. 2017 Nov;16(6):433-444. doi: 10.1002/pst.1822. Epub 2017 Aug 25.
Many new anticancer agents can be combined with existing drugs, as combining a number of drugs may be expected to have a better therapeutic effect than monotherapy owing to synergistic effects. Furthermore, to drive drug development and to reduce the associated cost, there has been a growing tendency to combine these as phase I/II trials. With respect to phase I/II oncology trials for the assessment of dose combinations, in the existing methodologies in which efficacy based on tumor response and safety based on toxicity are modeled as binary outcomes, it is not possible to enroll and treat the next cohort of patients unless the best overall response has been determined in the current cohort. Thus, the trial duration might be potentially extended to an unacceptable degree. In this study, we proposed a method that randomizes the next cohort of patients in the phase II part to the dose combination based on the estimated response rate using all the available observed data upon determination of the overall response in the current cohort. We compared the proposed method to the existing method using simulation studies. These demonstrated that the percentage of optimal dose combinations selected in the proposed method is not less than that in the existing method and that the trial duration in the proposed method is shortened compared to that in the existing method. The proposed method meets both ethical and financial requirements, and we believe it has the potential to contribute to expedite drug development.
许多新型抗癌药物可与现有药物联合使用，由于协同效应，多种药物联合使用可能比单一疗法具有更好的治疗效果。此外，为推动药物研发并降低相关成本，将这些药物作为I/II期试验联合使用的趋势日益明显。关于评估剂量组合的I/II期肿瘤试验，在现有方法中，基于肿瘤反应的疗效和基于毒性的安全性被建模为二元结果，除非在当前队列中确定了最佳总体反应，否则无法招募和治疗下一组患者。因此，试验持续时间可能会延长到不可接受的程度。在本研究中，我们提出了一种方法，即在确定当前队列的总体反应后，根据使用所有可用观察数据估计的反应率，将II期部分的下一组患者随机分配到剂量组合中。我们通过模拟研究将所提出的方法与现有方法进行了比较。结果表明，所提出方法中选择的最佳剂量组合的百分比不低于现有方法，且所提出方法的试验持续时间比现有方法缩短。所提出的方法符合伦理和财务要求，我们相信它有潜力有助于加快药物研发。
