Abstract A92: Murine clinical trials program

Abstract

Abstract Enormous advances in the biomedical sciences have raised tenable hope of a new era of personalized medicine. Significant hurdles to realizing this goal include the inordinately high and evolving degree of genetic and biologic diversity in carcinomas, even within categories of defined organ and cell-type. In addition, the tissue culture and xenograft preclinical model systems that have been instrumental in elucidating fundamental principles of cancer biology do not recapitulate the essential geometry or tissue and stromal interactions encountered in the native disease. As a result, the ability to kill cancer cells in these contexts has had limited impact on treating the diseases in patients. Genetically engineered mouse models of pancreas cancer appear to encompass the biological diversity and complexity seen in patients. In addition to revealing important aspects of disease pathobiology, these model systems form the basis of a preclinical platform, the Murine Clinical Trials Program (MCTP), designed to accelerate the development and evaluation of early detection, chemoprevention and therapeutic strategies most likely to impact patients in the clinic. By screening these strategies in highly faithful animal surrogates for the human disease, we hope to rapidly identify and translate the most effective approaches to the clinic, while concomitantly defining the appropriate disease subtype-specific context in which to employ each application. Attempting to accomplish these aims by performing initial validation and optimization experiments directly in patients can slow progress by many years, if not preclude it altogether. Treatment strategies are advanced through the MCTP in a systematic manner with defined endpoints and criteria (“Go/No-Go”) for each step. If these criteria are met in phase A (Pilot Study), they advance to Phase B (Full Survival Study). Strict enrollment criteria ensure the presence of invasive PDA (with or without metastatic disease) while also allowing sufficient time on investigational therapy to reveal potential resistance mechanisms, unanticipated secondary or off-target effects and delayed toxicities. Each of these aspects is described in detail in our presentation. Each new investigational agent in both the pilot and survival studies is analyzed in three arms: 1) agent alone; 2) agent + standard cytotoxic agent(s); 3) agent + cytotoxics + anti-stromal agent. In our standard approach, pilot studies enroll n=4-5 animals per agent. A 2-5 cm mass measurable by high-resolution ultrasound is required for enrollment. The standard 3 weeks ‘on’/1 week ‘off’ treatment regimen used routinely in patients is recapitulated in mice, together with a dose and route designed to be as similar as possible to that anticipated for human patients. Primary endpoints for pilot studies (1-2 cycles of treatment) include objective response and cellular effects including tumor cell apoptosis and proliferation, immune cell responses, changes in content and character of ECM components, vessel density and cross-sectional diameter, and so on. Results from pilot studies are used to determine whether a full survival study is warranted. Examples of recent MCTP pilot and survival studies will be presented. Citation Format: J. Scott Brockenbrough, Libing Feng, Ingunn M. Stromnes, Kathleen E. DelGiorno, Martin C. Whittle, Carlos Cuevas, Ashley M. Dotson, Joseph S. Ryan, Shelley M. Thorsen, Sunil R. Hingorani. Murine clinical trials program. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A92.