Phase I Designs for Combined Immunotherapies in Cancer

描述（由申请人提供）：候选人2011年8月，我加入了弗吉尼亚大学（UVA）公共卫生科学系的转化研究和应用统计部门，担任助理教授。作为该部门的一员，我的大部分工作都与癌症研究及其应用有关。我目前的研究涉及联合化疗药物的I期临床试验的设计和分析，该试验已在NCI-designated UVA癌症中心的多项化疗药物启动的研究中实施。自从加入该部门以来，我一直是UVA癌症中心生物统计学共享资源的积极成员，为此我已经开始与癌症中心成员合作设计和分析临床数据。我在弗吉尼亚大学的教师职位需要独立和合作的研究组成部分。这个建议的一个目标是我的统计方法研究，以补充我的合作努力，我相信这可以在免疫治疗环境中实现。我向独立研究过渡的策略之一是作为一名学术研究者发展自己的重点领域。这项提议将使我能够利用我在第一阶段化疗设计中获得的专业知识，特别是联合药物，并将其转移到生物制剂的创新领域，特别是免疫治疗。由于免疫疗法在联合药物的I期设计方面非常不发达，因此有机会巩固作为学术研究人员在这一领域的作用。UVA是该地区领先的癌症免疫治疗中心，二十多年来一直是疫苗疗法的创新者。它是NCI-designated cancer center support grant（CCSG）支持的最强有力的项目之一。我的主要导师，克雷格Slingluff博士，通过他作为ECOG黑色素瘤委员会副主席和癌症免疫治疗学会教员的工作，在癌症免疫治疗方面发挥了全国性的领导作用。他协调了超过15个由制药商发起的黑色素瘤疫苗临床试验，其中大部分涉及我的研究。 共同导师Gina Petroni博士担任首席生物统计学家。顾问帕特里克狄龙博士希望扩大新型免疫治疗剂在乳腺癌中的应用。这些研究工作创造了在UVA的生物统计学家，可以对这些临床试验的设计和分析有重大贡献的需求。因此，我的职业目标是接受Slingluff和Petroni博士的指导，在该机构的癌症免疫治疗试验中担任领先的生物统计学家。研究本提案的总体目标是（1）开发第一阶段设计 对于癌症免疫疗法的组合，（2）获得免疫疗法生物学的基本概念理解，以便更好地理解组合之间的剂量-毒性和剂量-反应关系，以及（3）接受I期临床试验规划基础的监管过程的培训。将提出新的I期方法，以推进公认的I期方法：（1）通过开发考虑组合中部分已知剂量-毒性顺序的设计，用于生物制剂;（2）通过开发考虑反应的设计，用于组合，并且不假设最高安全剂量是生物活性方面最有希望的剂量。本提案的具体目标 是：1.使用基于模型的剂量反应估计开发免疫药物组合的I期设计。2.使用剂量反应的经验估计值，开发免疫药物组合的I期剂量探索设计。这个项目的职业发展计划将包括与我的指导团队的会议，正式的课堂培训，以及参加我的导师的实验室，研讨会和专业会议。培训的一部分将涉及弗吉尼亚大学医学院新的弗吉尼亚转化和监管科学中心（VCTRS）下的监管科学教学法。该培训将有助于开发高质量的I期设计，并希望将其有效地整合到药物开发过程中。培训计划的其余部分将涉及免疫治疗的指导，其中包括与强大的指导团队，教学法和统计咨询的免疫治疗项目由人道免疫治疗中心（HITC）的成员在UVA医学院领导的互动。

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.