Early phase clinical trials to identify optimal dosing and safety.
Early phase clinical trials to identify optimal dosing and safety.
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DOI：
10.1016/j.molonc.2014.07.025
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发表时间：
2015-05
影响因子：
6.6
通讯作者：
Abdul Razak AR
中科院分区：
文献类型：
--
作者：
Cook N;Hansen AR;Siu LL;Abdul Razak AR
早期临床试验的目的是确定研究药物或多药联合的推荐剂量和毒性特征。分子靶向药物（MTA）和免疫疗法具有与化疗不同的毒性，这些毒性通常不依赖于剂量，并且可能导致慢性且有时不可预测的副作用。因此，使用基于毒性终点的剂量递增方法可能不适合确定推荐剂量，替代参数（如药代动力学或药效学结局）可能是有吸引力的选择。提高安全性和优化给药的方法包括改进的临床前模型和评估、基于创新模型的设计和剂量递增策略、患者选择、使用扩展队列和扩展毒性评估。通过采用新的策略来解决MTA的不同特性来定制I期试验的设计，以促进这些药物的开发。本次审查将集中在安全性和剂量确定的限制，发生在MTA和免疫疗法的发展。此外，还提出了克服这些挑战的策略，以开发I期试验，从而更准确地确定推荐剂量并识别不良事件。
The purpose of early stage clinical trials is to determine the recommended dose and toxicity profile of an investigational agent or multi-drug combination. Molecularly targeted agents (MTAs) and immunotherapies have distinct toxicities from chemotherapies that are often not dose dependent and can lead to chronic and sometimes unpredictable side effects. Therefore utilizing a dose escalation method that has toxicity based endpoints may not be as appropriate for determination of recommended dose, and alternative parameters such as pharmacokinetic or pharmacodynamic outcomes are potentially appealing options. Approaches to enhance safety and optimize dosing include improved preclinical models and assessment, innovative model based design and dose escalation strategies, patient selection, the use of expansion cohorts and extended toxicity assessments. Tailoring the design of phase I trials by adopting new strategies to address the different properties of MTAs is required to enhance the development of these agents. This review will focus on the limitations to safety and dose determination that have occurred in the development of MTAs and immunotherapies. In addition, strategies are proposed to overcome these challenges to develop phase I trials that can more accurately define the recommended dose and identify adverse events.
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DOI：
10.1158/1078-0432.ccr-12-2620
发表时间：
2013-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
DeMichele A;Berry DA;Zujewski J;Hunsberger S;Rubinstein L;Tomaszewski JE;Kelloff G;Perlmutter J;Buxton M;Lyandres J;Albain KS;Benz C;Chien AJ;Haluska P;Leyland-Jones B;Liu MC;Munster P;Olopade O;Park JW;Parker BA;Pusztai L;Tripathy D;Rugo H;Yee D;Esserman L
通讯作者：
Esserman L
影响因子：
5.7
作者：
Hidalgo M;Bruckheimer E;Rajeshkumar NV;Garrido-Laguna I;De Oliveira E;Rubio-Viqueira B;Strawn S;Wick MJ;Martell J;Sidransky D
通讯作者：
Sidransky D
影响因子：
64.8
作者：
Chen, Zhao;Cheng, Katherine;Walton, Zandra;Wang, Yuchuan;Ebi, Hiromichi;Shimamura, Takeshi;Liu, Yan;Tupper, Tanya;Ouyang, Jing;Li, Jie;Gao, Peng;Woo, Michele S.;Xu, Chunxiao;Yanagita, Masahiko;Altabef, Abigail;Wang, Shumei;Lee, Charles;Nakada, Yuji;Pena, Christopher G.;Sun, Yanping;Franchetti, Yoko;Yao, Catherine;Saur, Amy;Cameron, Michael D.;Nishino, Mizuki;Hayes, D. Neil;Wilkerson, Matthew D.;Roberts, Patrick J.;Lee, Carrie B.;Bardeesy, Nabeel;Butaney, Mohit;Chirieac, Lucian R.;Costa, Daniel B.;Jackman, David;Sharpless, Norman E.;Castrillon, Diego H.;Demetri, George D.;Jaenne, Pasi A.;Pandolfi, Pier Paolo;Cantley, Lewis C.;Kung, Andrew L.;Engelman, Jeffrey A.;Wong, Kwok-Kin
通讯作者：
Wong, Kwok-Kin
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2
作者：
GOODMAN, SN;ZAHURAK, ML;PIANTADOSI, S
通讯作者：
PIANTADOSI, S