Phase I Designs for Combined Immunotherapies in Cancer

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DESCRIPTION (provided by applicant): Candidate In August 2011, I joined the Division of Translational Research and Applied Statistics in the Department of Public Health Sciences at the University of Virginia (UVA) in the role of Assistant Professor. As a member of this division, the majority of my effort is related to cancer research and its applications. My current research involves the design and analysis of Phase I clinical trials for combined chemotherapeutic agents, which has already been implemented in multiple investigator-initiated studies for the NCI-designated UVA Cancer Center. Since joining the division, I have been an active member of the UVA Cancer Center Biostatistics Shared Resource, for which I have begun working with cancer center members on the design and analysis of clinical data. The faculty position I hold at UVA entails both an independent and collaborative research component. An objective of this proposal is for my statistical methodology research to complement my collaborative efforts, which I believe can be achieved in the immunotherapy setting. Part of my strategy for transitioning to research independence will be to develop my own area of focus as an academic investigator. This proposal would allow me to take the expertise I have acquired in Phase I design of chemotherapies, specifically with combined drugs, and move it into the innovative area of biological agents, and immunotherapy in particular. Because immunotherapy is very underdeveloped with regards to Phase I designs of combined drugs, an opportunity exists to solidify a role in this area as an academic researcher. Environment UVA is the leading cancer immunotherapy center in the region and has been an innovator in vaccine-based therapies for over two decades. It is one of the strongest programs supported in the NCI-designated cancer center support grant (CCSG). My primary mentor, Dr. Craig Slingluff, has a national leadership role in cancer immunotherapy through his work as vice chair of the melanoma committee for ECOG and as faculty of the Society for Immunotherapy of Cancer. He has coordinated over fifteen investigator-initiated clinical trials of melanoma vaccines, most of which have involved my co-mentor, Dr. Gina Petroni, as lead biostatistician. Consultant Dr. Patrick Dillon hopes to expand the use of novel immunotherapy agents in breast cancer. These research endeavors create a demand at UVA for a biostatistician that can have a significant contribution on the design and analysis of these clinical trials. Therefore, my career goals involve being mentored by Drs. Slingluff and Petroni to serve as a leading biostatistician in cancer immunotherapy trials at this institution. Research The overall goals of this proposal are to (1) develop Phase I designs for combinations of cancer immunotherapies, (2) gain a basic conceptual understanding of the biology of immunotherapy in order to better comprehend dose-toxicity and dose-response relationships between combinations and (3) receive training in the regulatory processes underlying the planning of Phase I clinical trials. New Phase I methods will be proposed that advance accepted Phase I methods (1) for biological agents by developing designs that account for the partially known dose-toxicity order among combinations and (2) for combinations by developing designs that account for response and do not assume that the highest safe dose is that which is most promising with regards to biologic activity. The specific aims for this proposal are: 1. Develop Phase I designs for immunologic agent combinations using model-based dose-response estimates. 2. Develop Phase I dose-finding designs for immunologic agent combinations using empiric estimates for dose-response. The career development plan for this project will consist of a combination of meetings with my mentoring team, formal classroom training, and participation in my mentor's laboratory, seminars and professional meetings. A portion of the training will involve didactics in regulatory science under the new Virginia Center for Translational and Regulatory Sciences (VCTRS) at the University of Virginia School of Medicine. This training will aid in the development of quality Phase I designs with the hopes of efficiently integrating them into the drug development process. The remainder of the training program will involve instruction in immunotherapy, which will include interaction with a strong mentoring team, didactics, and statistical consultation on immunotherapy projects lead by members of the Humane Immune Therapy Center (HITC) at the UVA School of Medicine.