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同种异体移植后的急性移植物抗宿主病（GVHD）。 造血细胞移植（HCT）。尽管采用了目前的预防策略，但仍有30 - 70%的接受者 发生急性GVHD。GVHD的发展是移植后发病率和非复发死亡率的主要原因。 同种异体HCT，并限制了患者的健康相关生活质量（HRQOL）及其恢复正常的能力。 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研究 组蛋白脱乙酰酶（HDAC）抑制（伏立诺他）以预防GVHD。在成人患者中，我们已经完成了一项 在相关供体中进行的首次人体I/II期试验，降低强度预处理同种异体HCT（NCT 00810602）， 和一项在无关供体中进行的II期试验，清髓性预处理异基因HCT（NCT 01790568）， 表明伏立诺他的安全性，可能减弱GVHD而不损害有益的移植物， 白血病（GVL）作用和潜在的神经保护作用（NCT 02409134）。儿科患者接受 同种异体HCT也可能受益于伏立诺他来预防GVHD，但面临着获得这种治疗的障碍。 可能挽救生命的治疗我们已经提交了申请，并从FDA获得了IND， 在儿科患者的标准GVHD预防之外，进行伏立诺他的I/II期试验 接受无关供体清髓性预处理HCT。这笔赠款的目的是资助第一/第二阶段 vorinostat在儿科HCT中的临床试验。研究的I期部分将招募至多12名年龄为3 - 12岁的受试者。 21年，并将使用3 + 3向上或向下确定vorinostat的推荐II期剂量（RP2D） 算法该研究的单组II期部分将招募另外37名受试者接受伏立诺他治疗 并将确定HCT后第100天II-IV级急性GVHD的发生率。的目标 这项在儿童HCT中进行的早期试验是为了评估剂量、安全性、药代动力学、药效学和 伏立诺他的RP2D。重要的其他终点包括相关实验室研究、认知功能、 和患者报告的HRQOL结局。我们假设伏立诺他抑制HDAC调节了 GVHD的炎症反应，并将与保留的认知和HRQOL相关。本研究将招募 儿科HCT患者的原因如下：1）存在设计良好的GVHD的主要未满足的需求 儿科HCT的临床试验，整合临床结局、生物学功能、认知评估和 HRQOL测量; 2）我们先前的HDAC抑制用于GVHD预防的临床前和临床数据， 成人HCT提供与作用机制相关的生物学相关性; 3）HDAC抑制可能具有 同种异体HCT治疗后，神经保护特性和HRQOL保持不变，已知这种治疗会对 认知功能，特别是在接受无关供体移植的患者中， 年龄较小的患者。因此，本提案将提供关于安全性、耐受性和 vorinostat在儿科HCT中的初步疗效，为未来全面试验的开发提供信息。

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.