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系統識別號 U0026-1107201111192000
論文名稱(中文) 癌症藥物第一期臨床試驗之最大耐受劑量的探討
論文名稱(英文) The study of the maximum tolerated dose in phase I oncology clinical trials
校院名稱 成功大學
系所名稱(中) 統計學系碩博士班
系所名稱(英) Department of Statistics
學年度 99
學期 2
出版年 100
研究生(中文) 黃羽緁
研究生(英文) Yu-Chieh Huang
學號 r26984099
學位類別 碩士
語文別 中文
論文頁數 49頁
口試委員 指導教授-杜宜軒
口試委員-黃錦輝
口試委員-吳雅琪
中文關鍵字 癌症藥物  第一期臨床試驗  3+3試驗  最大耐受劑量 
英文關鍵字 cancer drugs  phase I oncology clinical trials  3+3 design  maximum tolerated dose 
學科別分類
中文摘要 第一期臨床試驗的目的是針對新的藥物評估人體可以容忍其最大毒性的劑量,也就是最大耐受劑量。癌症藥物的毒性因為比一般藥物強,所以在癌症藥物第一期臨床試驗中會特別探討受測病人毒性反應的情形,基於保護病人的道德立場上,期望在試驗中的受測者人數可以達到最小。3+3試驗(Storer,1989)是癌症藥物第一期臨床試驗中常會使用到的臨床試驗,其試驗中各步驟下的藥物劑量水準是必須在試驗之前就決定好的。目前文獻中所提及的還有以3+3試驗為準則所衍生出來的5+3試驗(Gordon et al., 2001)、2+4試驗(Lee et al., 2009)、3+3+3試驗(Lee et al., 2009)以及3+1+1試驗(Storer, 2001),但都未曾針對這些試驗間進行比較。在本論文中考慮符合現實中的試驗情形,以模擬的方式進行3+3試驗與其類似試驗間的探討與比較。
英文摘要 The main purpose of the phase I clinical trial is to assess the highest possible but still tolerable dose of a new drug with respect to some prespecified dose-limiting toxicity, which is also defined as maximum tolerated dose (MTD). The anti-cancer drugs are cytotoxic agents which are more toxic than the usually pharmaceutical agents for treatment of other diseases. Therefore, the guiding principle for dose escalation in phase I cancer clinical trial is to minimize exposure of subjects to the intervention. A traditional 3+3 design (Storer, 1989) is usually conducted in phase I cancer clinical trial to find the MTD. It is easy to conduct by the investigators and the testing dose levels are prespecified. There are some modified designs based on the 3+3 design, such as the 5+3 design (Gordon et al., 2001), the 2+4 design (Lee et al., 2009), the 3+3+3 design (Lee et al., 2009) and 3+1+1 design (Storer, 2001). In this research, we will discuss and compare the properties that the investigators might be interested based on the simulation study.
論文目次 第一章 緒論 1
第二章 常見的試驗與藥物劑量決策回顧 3
第一節 劑量限制毒性與藥物劑量決策 3
第二節 3+3試驗 5
第三節 5+3試驗 7
第四節 2+4試驗 9
第五節 3+3+3試驗 11
第六節 3+1+1試驗 14
第三章 模擬設計 17
第一節 WEIBULL分配的累積分布函數 17
第二節 LOGISTIC曲線 22
第四章 結果探討 24
第一節 WEIBULL分配的累積分布函數 24
第二節 LOGISTIC曲線 34
第五章 結論與建議 44
參考文獻 46
附錄 47
參考文獻 [1] Adelman, D. C., Benjamin, R., Gordon, M. S., Holmgren, E. Jr., Margolin, K., Shak, S., Sledge, G. W., Stalter, S., Talpaz, M. (2001). Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin. Oncol, 19, 843-850.
[2] Adrian, M. S. (2010). Information needed to conduct first-in-human oncology trials in the United States: a view from a former FDA medical reviewer. Clin Cancer Res, 16, 1719-1725.
[3] Arbuck, S. G., Christian, M. C., Collins, J., Freidlin, B., Rubinstein, L., Simon, R. (1997). Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst, 89, 1138-1147.
[4] Bonneterre, J., Duhamel, A., Ferte, C., Isambert, N., Leblond, P., Penel, N. (2009). “Classical 3+3 design“ versus “accelerated titration designs“: analysis of 270 phase I trials investigating anti-cancer agents. Invest New Drugs, 27, 552-556.
[5] Christian, M., Eisenhauer, E. A., Humphrey, J. S., O’Dwyer, P. J. (2000). Phase I Clinical Trial Design in Cancer Drug Development. J Clin Oncol, 18, 684-692.
[6] Lee, J. J., Siu, L. L., Tourneau, C. L. (2009). Dose Escalation Methods in Phase I Cancer Clinical Trials. J Natl Cancer Inst, 101, 708-720.
[7] O’Quigley, J., Pepe, M., Fisher, L. (1990). Continual reassessment method:a practical design for phase I clinical trials in cancer. Biometrics, 46, 33-48.
[8] Omura, G. A. (2003).Modified Fibonacci Search. J Clin. Oncol, 21, 3177.
[9] Schneiderman, M. A. (1967). Mouse to man: Statistical problems in bringing a drug to clinical trial. Proceedings of the Fifth Berkeley Symposium on Mathematical Statistics and Probability , 4, 855-866.
[10] Storer, B. E. (1989). Design and analysis of phase I trials. Biometrics, 45, 925-937.
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