癌症標靶藥的早期臨床試驗目的在於估計該標靶藥的最佳生物劑量，讓服用該劑量的病患發生劑量限制毒性的機率低於設定的目標毒性機率，但是有最大的機率出現藥效反應。本文針對上述早期臨床試驗提出兩階段設計，第一階段中應用目前第一期臨床試驗設計中方便執行且表現頗佳的模式輔助設計mTPI-2，根據二元毒性反應資料進行快速且安全的調適性劑量配置。第二階段則進行世代試驗，先決定具有可接受毒性的劑量水準集合，然後根據二元的藥效反應資料在該集合中尋找最佳生物劑量。若毒性過強或藥效不足而提前中止試驗，則宣稱該標靶藥無效；若試驗繼續進行，則決定合適劑量水準，然後分別使用調適性或平衡設計隨機配置病人服用劑量。等病患人數達到預定數量，則中止試驗，進行最佳生物劑量的貝氏估計。因應第二階段不同的劑量配置方法，所提的兩階段設計分別記為mTPI2-ARD與mTPI2-BRD。本文針對毒性晚發或藥效延遲的情形，為更能有效縮短試驗的時間，進一步修正上述兩階段設計，分別記為mTPI2L-ARD與mTPI2L-BRD。本文提出的兩階段設計根據累積的毒性與藥效反應資料調整病患使用的劑量，不但降低病患接受過毒劑量的風險且提高病患接受有效劑量的機率。所提的設計無需假設特定的劑量毒性或劑量藥效模式，僅對毒性機率及藥效機率建立共軛先驗分布，進行貝氏分析，故為模式輔助兩階段設計。最後本文在各種不同的毒性機率與藥效機率的組合情境下進行模擬，比較本文的模式輔助之兩階段設計與目前的單劑量漸增設計或傳統兩階段設計的表現。模擬結果顯示本文提出的設計在正確估計最佳生物劑量與合理的配置劑量方面與其他早期臨床設計具有競爭力，同時在時間成本的控管方面優於單劑量漸增設計。;Early phase clinical trials for cancer research aim to estimate the optimal biologic dose (OBD) of the targeted drug under study where the OBD is the dose gives the largest efficacy probability but the toxicity probability is less than the targeted toxicity probability (TTP). Two-stage designs are considered for the early phase clinical trials. In the first stage, the mTPI-2 design is used to adaptively assign doses to patients based on the binary data of toxicity. In the second stage, cohort design is employed where the set of dose levels with acceptable toxicity is determined, and then the OBD is found in the set based on the efficacy response. The trial is early terminated and declared invalid if the toxicity is too strong or the effect is insufficient. If the trial continues, appropriate dose levels are determined and patients are randomly assigned adaptively or balancedly. When the number of patients reaches a predetermined number, we stop the trial and estimate the OBD. Since there are two different randomized designs in the second stage, the two-stage designs are denoted as mTPI2-ARD and mTPI2-BRD, respectively. This article also modify the two-stage designs for the situation with late-onset toxicity or delayed effect in order to shorten the trial time as denoted by mTPI2L-ARD and mTPI2L-BRD, respectively. The proposed two-stage designs, adaptively escalating doses based on the accumulated toxicity and efficacy responses, not only reduce the risk of assigning over-toxic doses to patients but also increase the probability of patients receiving effective doses. Moreover, the proposed designs do not assume any specific dose-toxicity or dose-efficacy model. In fact, the proposed designs are model-assisted two-stage designs because they use only a conjugate prior distributions for the toxicity probability and the efficacy probability in the Bayesian analysis. Finally, the performances of the two-stage designs comparing to the single-dose ascending designs or the previous two-stage design are investigated in a simulation study under various scenarios of toxicity and efficacy probabilities. The results of the simulation study show that the proposed two-stage designs are competitive to other early clinical designs in estimating the OBD with more rational dose assignment and outperform the competitive single-dose ascending designs in time management.
