Phase I/II clinical trial of HDAC inhibition for GVHD prevention in children, adolescents, and young adults

摘要 需要新的预防方法来预防异基因移植后急性移植物抗宿主病(GVHD) 造血细胞移植(HCT)。尽管目前采取了预防措施，但仍有30%-70%的接受者 发生急性移植物抗宿主病。移植物抗宿主病的发生是术后发病率和无复发死亡的主要原因 异基因血细胞移植，并限制了患者的健康相关生活质量(HRQOL)及其恢复到 日常生活活动。在过去的二十年里，我们的多学科团队一直在调查 组蛋白脱乙酰酶(HDAC)抑制(伏立诺)预防移植物抗宿主病。在成年患者中，我们完成了一项 首次在亲属供者中进行人类I/II期试验，降低强度条件下的同种异体红细胞移植(NCT00810602)， 和非血缘关系供者的第二阶段试验，清髓性条件下异基因红细胞移植(NCT01790568)，两者 提示涡流调节器的安全性，在不损害有益的移植物抗宿主病的情况下可能减弱移植物抗宿主病 白血病(GVL)效应和潜在的神经保护作用(NCT02409134)。接受手术的儿科患者 同种异体血细胞移植也可能受益于涡旋剂，以预防GVHD，但面临着获得这一点的障碍 有可能挽救生命的疗法。我们已经提交了申请，并从FDA获得了IND 在儿科患者接受标准GVHD预防的基础上，进行一项伏立诺的I/II期试验 正在接受非血缘关系供者清髓调节的HCT。这笔赠款的目的是为第一/第二阶段提供资金。 伏立诺在儿童红细胞压积中的临床应用这项研究的第一阶段将招收12名3岁以下的受试者。 21年，并将使用3+3向上或向下确定推荐的第二阶段涡流调节剂剂量(RP2D) 算法。该研究的单臂第二阶段部分将招募另外37名受试者接受涡流仪治疗 并将确定HCT后第100天II-IV级急性移植物抗宿主病的发生率。的目标是 这项儿科HCT的早期试验旨在评估剂量、安全性、药代动力学、药效学和 RP2D的涡流调节器。重要的附加终点包括相关的实验室研究、认知功能、 以及患者报告的HRQOL结果。我们假设，用涡流调节器抑制HDAC调节 GVHD的炎症反应，并将与保留的认知和HRQOL相关。这项研究将被录取 儿童HCT患者的原因如下：1)设计良好的GVHD的主要需求尚未得到满足 儿科HCT的临床试验综合了临床结果、生物功能、认知评估和 HRQOL测量；2)我们先前的临床前和临床资料：抑制HDAC预防GVHD 成人Hct提供与作用机制相关的生物学关联；3)HDAC抑制可能 异基因HCT后的神经保护特性和HRQOL的保存，这是一种已知的负面影响的治疗 认知功能，特别是接受无关供体移植的患者，可能是最重要的 较年轻的老年患者。因此，这项提案将提供关于安全性、耐受性和 涡流调节剂在儿童HCT中的初步疗效，为未来全面试验的发展提供信息。

ABSTRACT New prophylactic approaches are needed to prevent acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Despite prophylaxis with current strategies, 30-70% of recipients still develop acute GVHD. Development of GVHD is the leading cause of morbidity and non-relapse mortality after allogeneic HCT, and limits the health-related quality of life (HRQOL) of patients and their ability to return to activities of daily living. Over the last two decades, our multidisciplinary team has been investigating the use of histone deacetylase (HDAC) inhibition (vorinostat) to prevent GVHD. In adult patients, we have completed a first-in-human phase I/II trial in related donor, reduced intensity conditioning allogeneic HCT (NCT00810602), and a phase II trial in unrelated donor, myeloablative conditioning allogeneic HCT (NCT01790568), both indicating safety of vorinostat, possible attenuation of GVHD without compromising the beneficial graft versus leukemia (GVL) effect, and potential neuroprotective effects (NCT02409134). Pediatric patients undergoing allogeneic HCT may also benefit from vorinostat to prevent GVHD, but have faced barriers of access to this potentially life-saving therapy. We have already submitted an application and obtained an IND from the FDA to conduct a phase I/II trial of vorinostat in addition to standard GVHD prophylaxis for pediatric patients undergoing unrelated donor myeloablative conditioning HCT. The purpose of this grant is to fund the phase I/II clinical trial of vorinostat in pediatric HCT. The phase I portion of the study will enroll up to 12 subjects aged 3– 21 years and will determine the recommended phase II dose (RP2D) of vorinostat using a 3+3 up-or-down algorithm. The single-arm phase II portion of the study will enroll an additional 37 subjects to receive vorinostat at the RP2D and will determine the incidence of grade II-IV acute GVHD at day 100 post-HCT. The objective of this early phase trial in pediatric HCT is to assess dose, safety, pharmacokinetics, pharmacodynamics, and the RP2D of vorinostat. Important additional endpoints include correlative laboratory studies, cognitive function, and patient-reported outcomes of HRQOL. We hypothesize that HDAC inhibition with vorinostat regulates the inflammatory response of GVHD and will correlate with preserved cognition and HRQOL. This study will enroll pediatric HCT patients for the following reasons: 1) There is a major unmet need of well-designed GVHD clinical trials in pediatric HCT that integrate clinical outcomes, biological function, cognitive assessments, and HRQOL measures; 2) Our previous pre-clinical and clinical data of HDAC inhibition for GVHD prevention in adult HCT provide biological correlates with relevance for mechanism of action; 3) HDAC inhibition may have neuroprotective properties and preserve HRQOL after allogeneic HCT, a treatment known to negatively impact cognitive function, particularly in patients receiving unrelated donor grafts, and potentially most significant in younger aged patients. Thus, this proposal will provide critical information on the safety, tolerability and preliminary efficacy of vorinostat in pediatric HCT to inform the development of a future, full-scale trial.