Abstract 1206: Parameters influencing the design of mouse clinical trial (HuTrialTM)
Authors: Guo Sheng , Wang Zhun , Chen Dawei , Yang Jie , Yang Mengmeng , Huang Xuesong , Wery Jean-Pierre , Li Henry 
Published: May 2015

Abstract
Patient derived xenograft (PDX or HuPrime®) is believed to best mimic original human cancers from which the models were derived. PDX becomes popular to evaluate cancer drug for better predictive power. Cancers are diverse for their molecular pathogenesis and different in response to treatment. Multiple subjects are always needed in clinical evaluation, which is also true in PDX. Mouse clinical trial (MCT), or HuTrialTM, mimics phase II clinical trial, involving multiple subjects. MCT can be used for drug position and biomarker discovery. A large number of PDXs have been created globally from diverse cancer patients, enabling MCT. MCT offers advantages over human trial: a) complex tests (e.g. new agents, high dose, complex combinations, the same subject repeatedly, and no need for early stop before completion,...) can readily be performed with significant less regulatory constraints; b) any single subject can be assigned to different treatment arms, enabling internal control and enhancing statistic power; c) the endpoints can be objectively defined and measured; d) healthy inbred mice can guarantee consistent drug exposure, avoiding PK and/or other non-tumor related variations; and e) the potential savings in later clinical trial due to reduction in size and improving success.
Randomized and controlled trial (RCT) with statistic power, as a gold standard in the clinic, can also be applied in MCT design and implementation, in order to enable reliable data analysis and conclusion. In addition, the commonly used clinical endpoints can also been tested in MCT, including Response Evaluation Criteria in Solid Tumors (RECIST: CR, PR, SD, PD) and survival (PFS, OS, HR, MST), besides those commonly used in mouse study, e.g. T/C, TGI, etc. We have created a large library of PDX models (1, 2), and also been testing them for drug evaluation in a MCT format (2) for confirming indication and discovering predictive biomarker. In this study, we have specifically compared the clinic endpoint and the endpoints used in MCT, and also investigated the potential parameters that can influence the study design by retrospectively analyzing our historic MCT studies. Our result can help us to design clinic-relevant endpoint and reveal the parameters influencing trial data integrity: 1) # of models and # mice per arm needed; 2) the potency of test article, as measured by hazard ratio or HR, on mouse # requirement; 3) tumor growth rate on response (ΔT/ΔC) or on “survival” endpoint (time to event). Our data so far seem to point to that response endpoint are correlated with “survival endpoint”in general. HR seems not correlated with tumor growth rate. The smaller HR, the lower the # mice per arm is needed. These observations can be useful in facilitating future MCT design.
References
1. Yang et al. Int J Cancer. 2013;132:E74-84.
2. Zhang et al. Sci Rep. 2013;3:2992.
Citation Format: Sheng Guo, Zhun Wang, Dawei Chen, Jie Yang, Mengmeng Yang, Xuesong Huang, Jean-Pierre Wery, Henry Li. Parameters influencing the design of mouse clinical trial (HuTrialTM). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1206. doi:10.1158/1538-7445.AM2014-1206