| 摘要: | 因為個別藥品從不同路徑抑制腫瘤細胞的成長或是抗藥性的生成，為提高癌症治療效果經常研發混合兩種或多種抗癌藥的複合藥。複合藥可能因為個別藥效的加乘作用提高藥效，當個別藥劑量相關毒性重疊時毒性也可能提升，因此建立優良早期臨床試驗鑑別具有可容忍毒性且達到最高藥效的最佳劑量組合是一個發展複合藥的重要議題。目前複合藥研究聚焦於合併考量毒性與藥效反應，根據世代完整受試結果調適性決定下一世代受試劑量組合的設計。當藥效反應需時較長，此一設計將耗費過長的試驗時間。本計畫為縮短試驗時間考量二階段試驗設計，在第一階段尋求複合藥具有可容忍毒性的可接受劑量組合，在第二階段調適且隨機配置成批受試者服用可接受且藥效較佳的劑量組合，然後根據所得資料鑑別複合藥最佳劑量組合。臨床試驗毒性反應是二元變數，但是藥效反應可能是二元變數或存活時間。此外目前發展包含混合二種化療藥或兩種標靶藥的複合藥、混合化療藥與標靶藥或混合標靶藥與免疫療法的複合藥，可能其中一種是固定劑量的標準藥而另一種是添加藥，也可能是互相混合的藥品。此二年期計畫分年針對混合兩種藥的複合藥及混合標準藥與添加藥的複合藥，在不同藥效反應變數下鑑別複合藥的最佳劑量組合。 ;In order to improve the drug efficacy for cancer treatment, the drug development recently considers the combination of two or more anticancer drugs, especially when individual drugs target different pathways and/or inhibit resistance mechanisms in the tumor-malignant process. Although the efficacy of the combined drugs could be improved due to the expected synergistic treatment effects, the toxicity of the combined drugs may be enhanced when individual drugs possibly have overlapping dose-limiting toxicities (DLTs). Therefore, it is important to have well-designed phase I/II trials for finding the optimal combination doses (OCD) so that the combined drugs preserve the maximum efficacy, while maintaining allowable toxicity. Note that the dose-finding study for combined drugs majorly focus on sequentially and adaptively searching for a better drug combination for next cohort of patients based on both the completely observed responses of toxicity and efficacy. However, when the efficacy response takes a long time to observe, the trial time of the sequential dose-finding design would be too lengthy. Therefore, in this project, innovative two-stage designs are considered in which admissible dose combinations with allowable toxicity are identified in the first stage, and, in the second stage, batches of more patients are adaptively and randomly allocated to receive more effective yet admissible dose combinations. Finally, the OCD is identified based on all the available toxicity and efficacy responses. Note that the toxicity response in clinical trial is usually the binary variable, but the type of efficacy response may be binary variable or survival time. Also, note that combined drugs under study recently include a combination of two chemotherapies or two molecular targeting agents (MTAs), a combination of a chemotherapy and an MTA, or a combination of an MTA and immunotherapy (IMT), where one of the two drugs may serve as the standard therapy with a fixed dose and the other is the additive drug, or the two therapies under current use are combined. Therefore, in the first year of the subproject, novel two-stage early clinical trial designs are constructed for finding the OCD with different types of efficacy response when two anti-cancer therapies are combined. In the second year, novel two-stage phase I/II trial designs are developed for finding the OCD with different types of efficacy response when a standard therapy is combined with an additive drug. In fact, the optimal dose of the additive drug is determined so that the combined drug is more effective than the standard therapy while maintains the allowable toxicity. |
