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

HDAC 抑制预防儿童、青少年和年轻人 GVHD 的 I/II 期临床试验

基本信息

批准号：
10654695
负责人：
SUNG WON CHOI
金额：
$ 43.56万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654695
关键词：
Activities of Daily Living Acute Graft Versus Host Disease Adolescent and Young Adult Adult Age Algorithms Allogenic Attenuated Biological Biological Process Biological Products Cell-Mediated Cytolysis Child Childhood Clinical Clinical Data Clinical Trials Cognition Complication Coupled Data Development Disadvantaged Dose Drug Kinetics Enrollment Functional disorder Funding Funding Opportunities Future Goals Grant Hematology Histone Deacetylase Inhibitor Immunosuppression Impaired cognition Incidence Inflammatory Inflammatory Response Infrastructure Intervention Knowledge Laboratory Study Life Malignant - descriptor Maximum Tolerated Dose Measures Morbidity - disease rate Neurocognitive Outcome Patient Outcomes Assessments Patient Self-Report Patients Pharmacodynamics Phase Phase I/II Clinical Trial Phase I/II Trial Population Prevention strategy Property Prophylactic treatment Randomized Controlled Clinical Trials Recommendation Regulatory T-Lymphocyte Research Resources Role Safety Sampling Societies T-Lymphocyte Testing Tissues Transplant Recipients Transplantation Vorinostat Work aged arm attenuation clinical practice cognitive function cognitive testing conditioning curative treatments cytokine design disorder prevention early phase trial effective therapy first-in-human graft vs host disease graft vs leukemia effect health related quality of life hematopoietic cell transplantation immunomodulatory therapies improved insight investigator-initiated trial member mortality mouse model multidisciplinary neuroprotection novel novel strategies novel therapeutics patient population pediatric patients phase II trial pre-clinical preclinical study preservation prevent prevention clinical trial prophylactic public health relevance skills targeted agent

项目摘要

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.

抽象的需要新的预防方法来预防同种异体移植后发生急性移植物抗宿主病（GVHD）尽管采用目前的策略进行预防，但仍有 30-70% 的受者接受造血细胞移植。发生急性 GVHD。GVHD 的发生是术后发病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) 及其恢复能力在过去的二十年里，我们的多学科团队一直在研究日常生活活动的使用。我们已经完成了一项针对成年患者的组蛋白脱乙酰酶 (HDAC) 抑制（伏立诺他）预防 GVHD 的研究。在相关供体中进行的首次人体 I/II 期试验，降低强度调节同种异体 HCT (NCT00810602)，以及一项针对无关供体、清髓性调理同种异体 HCT 的 II 期试验 (NCT01790568)，两者均表明伏立诺他的安全性，可能在不损害有益移植物的情况下减弱 GVHD 白血病（GVL）效应和潜在的神经保护作用（NCT02409134）。同种异体 HCT 也可能受益于伏立诺他来预防 GVHD，但面临着获取障碍我们已经向 FDA 提交了申请并获得了 IND。除了对儿科患者进行标准 GVHD 预防外，还进行伏立诺他的 I/II 期试验接受无关的供体清髓性 HCT 这笔赠款的目的是为 I/II 期提供资金。伏立诺他在儿科 HCT 中的临床试验该研究的 I 期部分将招募最多 12 名 3 岁以下的受试者。 21 年，将使用 3+3 向上或向下确定伏立诺他的推荐 II 期剂量 (RP2D) 该研究的单臂 II 期部分将另外招募 37 名受试者接受伏立诺他治疗。 RP2D 并将确定 HCT 后第 100 天 II-IV 级急性 GVHD 的发生率。这项儿童 HCT 的早期试验旨在评估剂量、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、我们勇敢地说，伏立诺他抑制 HDAC 可以调节 HRQOL。 GVHD 的炎症反应，并将与保留的认知和 HRQOL 相关。儿科 HCT 患者的原因如下： 1) 精心设计的 GVHD 的需求尚未得到满足儿科 HCT 的临床试验，整合了临床结果、生物功能、认知评估和 HRQOL 措施；2) 我们之前的 HDAC 抑制预防 GVHD 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（一种已知会产生负面影响的治疗方法）后神经保护特性并保持 HRQOL 认知功能，特别是在接受不相关的供体移植物的患者中，并且可能在以下方面最重要：因此，该提案将提供有关安全性、耐受性和安全性的重要信息。伏立诺他在儿科 HCT 中的初步疗效为未来全面试验的发展提供信息。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Positive psychology interventions for family caregivers coping with cancer: Who will use them?

DOI：
10.1177/20551029231224358
发表时间：
2023-07
期刊：
Health psychology open
影响因子：
2.9
作者：
通讯作者：

A Systematic Review of Machine Learning Techniques in Hematopoietic Stem Cell Transplantation (HSCT).

DOI：
10.3390/s20216100
发表时间：
2020-10-27
期刊：
Sensors (Basel, Switzerland)
影响因子：
0
作者：
Gupta V;Braun TM;Chowdhury M;Tewari M;Choi SW
通讯作者：
Choi SW

Electronic Health Record Portal Use by Family Caregivers of Patients Undergoing Hematopoietic Cell Transplantation: United States National Survey Study.

DOI：
10.2196/26509
发表时间：
2021-03-09
期刊：
JMIR cancer
影响因子：
2.8
作者：
Gupta V;Raj M;Hoodin F;Yahng L;Braun T;Choi SW
通讯作者：
Choi SW

Risk Factors for COVID-19 in College Students Identified by Physical, Mental, and Social Health Reported During the Fall 2020 Semester: Observational Study Using the Roadmap App and Fitbit Wearable Sensors.

DOI：
10.2196/34645
发表时间：
2022-02-10
期刊：
JMIR mental health
影响因子：
5.2
作者：
Gilley KN;Baroudi L;Yu M;Gainsburg I;Reddy N;Bradley C;Cislo C;Rozwadowski ML;Clingan CA;DeMoss MS;Churay T;Birditt K;Colabianchi N;Chowdhury M;Forger D;Gagnier J;Zernicke RF;Cunningham JL;Cain SM;Tewari M;Choi SW
通讯作者：
Choi SW

Mobile Technology to Monitor and Support Health and Well-Being: Qualitative Study of Perspectives and Design Suggestions From Patients Undergoing Hematopoietic Cell Transplantation.