Phase II Trial of Vorinostat plus Tacrolimus and Mycophenolate to Prevent GVHD

伏立诺他联合他克莫司和霉酚酸酯预防 GVHD 的 II 期试验

• 批准号: 8591176
• 负责人: SUNG WON CHOI
• 金额: $ 13.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591176
• 关键词: Acute; Acute Graft Versus Host Disease; Allogeneic Bone Marrow Transplantation; Antigen-Presenting Cells; Area; Attenuated; Biology; Bone Marrow Transplantation; CD8B1 gene; Cells; Clinical; Clinical Data; Clinical Research; Clinical Trials; Complement; Complication; Conduct Clinical Trials; Correlative Study; Data; Deacetylase; Development; Diagnosis; Dioxygenases; Disease Pathway; Educational Curriculum; Ethics; Foundations; Goals; Grant; Growth; Hematological Disease; Histone Acetylation; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Human; Human Subject Research; Immunologics; Immunosuppression; Inflammation; Institution; Knowledge; Laboratories; Laboratory Study; Lead; Learning; Malignant - descriptor; Manuscripts; Master of Science; Mediator of activation protein; Mentors; Modality; Modeling; Morbidity - disease rate; Mus; Mycophenolate; Non-Malignant; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Plasma; Population; Preparation; Prevention; Prevention strategy; Process; Productivity; Prophylactic treatment; Regimen; Regulation; Research; Research Design; Research Personnel; Research Project Grants; Research Training; Resources; Role; Sampling; Severities; Structure; Supervision; T-Lymphocyte; Tacrolimus; Techniques; Testing; Therapeutic; Time; Training; Training Activity; Translating; Transplantation; Vorinostat; antitumor agent; career; career development; clinical practice; conditioning; design; disorder prevention; experience; graft vs host disease; high risk; improved; indoleamine; innovation; mortality; novel; older patient; patient oriented research; phase 2 study; pre-clinical; prevent; programs; skills; therapeutic target; trial comparing

DESCRIPTION (provided by applicant): The career development activities outlined in this K23 proposal will provide didactic and experiential training under a mentored experience in several areas new to Dr. Sung Choi. She will acquire biostatistical skills and knowledge in specific areas of clinical research, learn new laboratory techniques, and develop ethical principles and research integrity essential for the conduct of human subject research. Thus, the comprehensive curriculum will complement her existing skills with new and advanced techniques and approaches with the goal of developing an independent, patient-oriented research career as a translational investigator in the field of bone marrow transplantation (BMT). With support of the K23, Dr. Choi will conduct a mentored patient-oriented research project in alignment with her training activities and overall career goals. Allogeneic BMT is a potentially curative therapy for many non-hematologic and hematologic diseases. Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic BMT and prevents this curative therapy from wider application. Current pharmacologic agents for GVHD prevention and treatment primarily target an essential effector for GVHD, donor T cells. Other key effectors for GVHD, and therefore potential therapeutic targets, are antigen presenting cells (APCs). Therefore, agents that target the allostimulatory functions of APCs may be an innovative therapeutic potential in the GVH process. Histone deacetylase (HDAC) inhibitors are novel anti-tumor agents that appear to be well-tolerated in human clinical trials. However, their immunomodulatory effects have thus far been largely unrecognized. Pre-clinical data generated in the laboratory of Dr. Reddy, Dr. Choi's mentor, form the rationale for this proposal. Dr. Choi will test the central hypothesis that HDAC inhibition will reduce the severity of GVHD by suppressing the functions of human APCs, the key mediators of GVHD, in an innovative Phase II clinical trial. These studies could allow for the development of a novel class of immunomodulatory drugs for attenuating GVHD. The specific aims of the clinical trial are: 1) To conduct a Phase II trial using vorinostat in addition to standard immunosuppression to prevent GVHD in related donor reduced intensity conditioning (RIC) BMT. 2) To determine the cellular and plasma markers of deacetylase inhibition on inflammation after vorinostat administration following related donor RIC BMT. In summary, this K23 will provide Dr. Choi with the time and resources to: 1) execute a novel clinical trial and perform robust correlative studies within a well-defined mentoring structure; 2) obtain formal training in clinical research design and statistical analyses; 3) increase her research productivity; 4) develop skills in manuscript and grant preparation; and 5) evolve into an independent investigator. Allogeneic bone marrow transplantation is a potentially curative therapy for many malignant and nonmalignant conditions whose applicability has been impeded by the development of its most serious complication, graft-versus-host disease (GVHD). A novel preventive strategy to mitigate GVHD will allow for better harnessing of this effective therapeutic modality.

描述（由申请人提供）：本K23提案中概述的职业发展活动将在Sung Choi博士新的多个领域提供教学和体验培训。她将在临床研究的特定领域中获得生物统计学技能和知识，学习新的实验室技术，并发展道德原则和研究完整性，这对于进行人类学科研究至关重要。因此，全面的课程将通过新的和先进的技术和方法来补充她的现有技能，以发展独立的，以患者为导向的研究职业，成为骨髓移植（BMT）领域的转化研究者。在K23的支持下，Choi博士将与她的培训活动和整体职业目标保持一致的指导患者的研究项目。同种异体BMT是许多非血液学和血液学疾病的潜在治疗疗法。同种异体BMT后，移植物抗宿主病（GVHD）仍然是发病率和死亡率的主要原因，并防止这种治疗疗法更广泛。当前用于GVHD预防和治疗的药理学剂主要针对GVHD，供体T细胞的基本效应子。 GVHD的其他关键效应因素，因此是潜在的治疗靶标，是抗原呈递细胞（APC）。因此，针对APC的同种刺激功能的药物在GVH过程中可能是创新的治疗潜力。组蛋白脱乙酰基酶（HDAC）抑制剂是在人类临床试验中似乎耐受性良好的新型抗肿瘤药。但是，到目前为止，它们的免疫调节作用在很大程度上未被认可。 Choi博士的导师Reddy博士在实验室中产生的临床前数据构成了该建议的理由。 Choi博士将在一项创新的II期临床试验中抑制Human APC的功能（GVHD的关键介体）人APC的功能来降低GVHD的严重性。这些研究可以允许开发一种新型的免疫调节药物来减弱GVHD。临床试验的具体目的是：1）除标准免疫抑制外，还要使用伏诺替纳斯特进行II期试验，以防止相关供体降低强度调节（RIC）BMT的GVHD。 2）确定相关供体RIC BMT后伏地施用后脱乙酰基酶抑制炎症的细胞和血浆标记。总而言之，该K23将为Choi博士提供时间和资源：1）执行新的临床试验，并在定义明确的指导结构中进行强大的相关性研究； 2）获得临床研究设计和统计分析的正式培训； 3）提高她的研究生产率； 4）发展手稿和赠款准备技能； 5）演变成独立的研究者。同种异体骨髓移植是一种潜在的治疗疗法，用于许多恶性和非恶性疾病，其适用性受到其最严重的并发症，移植物与宿主疾病（GVHD）的发展所阻碍。缓解GVHD的新型预防策略将使您更好地利用这种有效的治疗方式。