Mount Sinai Core Clinical Consortium for the BMT Clinical Trials Network

BMT 临床试验网络西奈山核心临床联盟

• 批准号: 10429967
• 负责人: JOHN LEVINE
• 金额: $ 17.33万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-27 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429967
• 关键词: Acute Graft Versus Host Disease; Age; Allogenic; Antithymoglobulin; Biological Markers; Blood; Blood specimen; Bone Marrow Transplantation; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Network; Complication; Conduct Clinical Trials; Development; Disease; Dose; Early Diagnosis; Early treatment; Enrollment; Excision; FDA approved; Gastrointestinal tract structure; Goals; Graft Rejection; Hematological Disease; Immunosuppression; Infection; Inflammatory Bowel Diseases; Intervention; Leadership; Life; Mission; Monoclonal Antibodies; Non-Malignant; Patient Selection; Patient-Focused Outcomes; Patients; Pharmacology; Prevention; Prevention strategy; Productivity; Refractory; Regimen; Relapse; Research Personnel; Risk; Risk Factors; Sickle Cell Anemia; Steroids; Symptoms; T-Cell Depletion; T-Lymphocyte; Tacrolimus; Testing; Transplant Recipients; Transplantation; Underrepresented Minority; base; conditioning; disorder prevention; gastrointestinal; graft vs host disease; high risk; high risk population; improved; improved outcome; innovation; mortality; novel; patient stratification; preempt; preference; trafficking; transplant centers

SUMMARY/ABSTRACT The Mount Sinai BMT CTN Consortium combines three large blood and marrow transplant (BMT) centers (Mount Sinai, Vanderbilt, and the Mayo Clinic; >900 total annual including >250 allogeneic BMT) with a strong track record of productivity within the BMT CTN. Our consortium possesses significant strengths to accomplish BMT CTN strategic goals including long-standing scientific leadership of the BMT CTN, high accrual to BMT CTN clinical trials, a proven ability to enroll large numbers of under-represented minorities in clinical trials, extensive expertise in transplant for non- malignant blood diseases (especially sickle cell disease), and a highly innovative, biomarker-based approach to graft versus host disease (GVHD), the principal complication of allogeneic BMT. Our investigators have developed and validated a novel GVHD-biomarker based score that stratifies patients on the basis of blood samples obtained seven days after BMT that separates patients into low risk and high risk groups for risk of severe GVHD and six month non-relapse mortality (NRM). The day 7 score accurately assigns risk regardless of donor type, degree of HLA-match, conditioning regimen, age, or use of thymoglobulin, making it ideal for testing a preemptive GVHD strategy in the multicenter BMT CTN setting. The majority of deaths in patients with a high risk day 7 score are due to steroid refractory gastrointestinal (GI) GVHD even though symptoms only occur weeks later. We thus propose a preemptive clinical trial to reduce steroid refractory GVHD in high risk patients. We expect such preemption will not increase relapse or deaths from other causes and thereby improve survival. To accomplish this goal, we propose to preemptively treat high risk patients with vedolizumab, a monoclonal antibody that targets α4β7+ T cells and inhibits their trafficking to the GI tract. Vedolizumab is FDA approved for inflammatory bowel disease and has already successfully been used in a small number of BMT patients with steroid refractory GI GVHD. A desirable attribute of our proposal is that testing this strategy in the patients most likely to develop steroid refractory GVHD will require fewer subjects to detect a beneficial effect. Our specific aims are: (1) To participate vigorously in BMT CTN clinical trials and committees and (2) To preemptively treat biomarker-defined high risk patients with vedolizumab to improve one-year steroid-refractory GVHD-free, relapse-free survival. RELEVANCE: The Blood and Marrow Transplant Clinical Trials Network conducts clinical trials to improve outcomes for patients facing life-threatening diseases. The Mount Sinai BMT CTN Consortium will advance the mission of the BMT CTN by enrolling patients onto BMT CTN clinical trials and providing scientific leadership to the BMT CTN. The proposed clinical trial will mitigate graft-versus-host disease, the most serious BMT complication.

摘要/摘要 西奈山 BMT CTN 联盟结合了三个大型血液和骨髓移植 (BMT) 中心（西奈山、范德比尔特和梅奥诊所；每年超过 900 个中心，其中包括超过 250 个同种异体中心） BMT）在 BMT CTN 中具有良好的生产力记录。我们财团拥有 实现 BMT CTN 战略目标（包括长期科学目标）的重要优势 BMT CTN 的领导地位、BMT CTN 临床试验的高累积率、经过验证的招募大量患者的能力 临床试验中代表性不足的少数群体数量，非移植方面的广泛专业知识 恶性血液病（尤其是镰状细胞病），以及一种高度创新的、基于生物标记物的 移植物抗宿主病 (GVHD) 是同种异体 BMT 的主要并发症。我们的 研究人员开发并验证了一种基于 GVHD 生物标志物的新型评分，该评分可对 根据 BMT 后 7 天获得的血液样本，将患者分为低 严重 GVHD 风险和六个月非复发死亡率 (NRM) 风险和高风险人群。那天 7 分准确地分配风险，无论捐赠者类型、HLA 匹配程度、预处理方案、 年龄或胸腺球蛋白的使用，使其成为在多中心测试先发性 GVHD 策略的理想选择 BMT CTN 设置。第 7 天评分高风险的患者大多数死亡是由类固醇引起的 难治性胃肠道 (GI) GVHD，即使症状仅在几周后出现。因此我们建议 一项旨在减少高危患者中类固醇难治性 GVHD 的先发性临床试验。我们期待这样的 先发制人不会增加复发或其他原因导致的死亡，从而提高生存率。到 为了实现这一目标，我们建议先用维多珠单抗（vedolizumab）治疗高危患者，维多珠单抗是一种 靶向 α4β7+ T 细胞并抑制其运输至胃肠道的单克隆抗体。维多珠单抗 已获得 FDA 批准用于治疗炎症性肠病，并已成功用于小规模治疗 患有类固醇难治性胃肠道 GVHD 的 BMT 患者数量。我们的提案的一个理想特征是 在最有可能发生类固醇难治性 GVHD 的患者中测试这一策略将需要更少的时间 受试者检测有益效果。我们的具体目标是：（1）积极参与BMT CTN 临床试验和委员会，以及 (2) 抢先治疗生物标志物定义的高风险患者 vedolizumab 可改善类固醇难治性无 GVHD、无复发的一年生存率。 相关性：血液和骨髓移植临床试验网络开展临床试验以 改善面临危及生命的疾病的患者的治疗结果。西奈山 BMT CTN 联盟 将通过招募患者参加 BMT CTN 临床试验来推进 BMT CTN 的使命， 为 BMT CTN 提供科学领导。拟议的临床试验将减轻移植物抗宿主 疾病，最严重的 BMT 并发症。