研發癌症新藥的第一期臨床試驗之主要目的是估計最大耐受劑量，其中服用該劑量的病患產生劑量限制毒性的機率最接近目標毒性機率。其次考量在劑量升降的試驗過程中，不宜分派過多病患服用無藥效的劑量，更要避免讓病患承擔過高的中毒風險，因此希望降低施予病患過低或過高劑量的機會。本文建議根據最大耐受劑量的後驗分布中位數建立劑量升降過程。當試驗病患人數用盡後，本文則建議參考最大耐受劑量後驗分布中位數與眾數選擇最大耐受劑量，以便提供第二期臨床試驗使用。因為本文研究的是根據後驗分布中位數及眾數的第一期臨床試驗設計，因此將此設計方法記作MEMO。本文針對MEMO試驗設計進行劑量的配置設計，使得MEMO試驗設計在應用上更加穩健，另外也針對晚發毒性的情形推廣MEMO試驗設計，獲得TITE-MEMO試驗設計。最後本文在各種不同的劑量毒性關係下，藉由模擬研究探討所提出的方法相對於改良毒性機率區間、連續重評估方法與改良嚴格控管過度劑量方法之表現。研究顯示，本文提出的方法在劑量升降過程中能合理的控制施予病患過高劑量的可能性，也能提供相對靠近真實最大耐受劑量的劑量給未來第二期的臨床試驗使用。;The major purpose of a phase I clinical trial is to estimate the maximum tolerated dose (MTD) of the drug at which the probability of the dose-limiting toxicity (DLT) is closest the targeted toxicity probability (TTP). Meanwhile, it is important to avoid assigning patients to less therapeutic doses and protect patients from overdosing in the dose escalation procedure. This article considers constructing the dose-escalation procedure based on the posterior medians of the MTD. When the maximum number of patients is reached, the MTD is then recommended by taking inference of the posterior median and mode of the MTD. Since the design involves both the posterior median and mode of the MTD, it is denoted by MEMO. The working doses for the MEMO design are calibrated based on the empirical power model for the dose-toxicity relationship. Moreover, the proposed design can be generalized to be TITE-MEMO for late-onset toxicity when data of time-to-event are available. A simulation study is finally conducted to compare the relative performance of the proposed designs to some competitive designs, for example, modified toxicity probability interval method, continual reassessment method and modified escalation with overdose control, dose assignment and MTD selection under a variety of scenarios of dose-toxicity relationship. The proposed designs generally produce a dose assignment that appropriately reduce the risk of overdose and give a recommendation of feasible MTD for the further phase II trial.
