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.

抽象的需要采用新的预防方法来预防同种元素后急性移植物抗宿主病（GVHD）造血细胞移植（HCT）。尽管预防了当前策略，但仍有30％至70％的接收者仍在发展急性GVHD。 GVHD的发展是发病率和非释放死亡率之后的主要原因同种异体HCT，并限制了患者与健康相关的生活质量（HRQOL）及其恢复的能力日常生活的活动。在过去的二十年中，我们的多学科团队一直在调查使用 Hisstone脱乙酰基酶（HDAC）抑制（Vorinostat）以防止GVHD。在成年患者中，我们已经完成了相关供体的第一阶段I/II试验降低强度调节同种异体HCT（NCT00810602），以及无关供体的II期试验，髓质条件同种异体HCT（NCT01790568）指示Vorinostat的安全性，可能会衰减GVHD，而不会损害有益的移植物与白血病（GVL）效应和潜在的神经保护作用（NCT02409134）。小儿患者正在接受同种异体HCT也可能受益于Vorinostat，以防止GVHD，但面临着障碍潜在的挽救生命的疗法。我们已经提交了申请，并从FDA获得了IND 除了针对小儿患者的标准GVHD预防外，还进行了Vorinostat的I/II期试验接受无关的供体髓质调节HCT。这笔赠款的目的是为I/II阶段提供资金小儿HCT中伏诺替纳斯特的临床试验。该研究的第一阶段部分最多将注册12名3-至年龄的受试者 21年，将使用3+3上下的Vorinostat的建议的II期剂量（RP2D）确定算法。研究的单臂II期部分将招募37名受试者接收伏地在RP2D上，将在HCT后100天确定II-IV急性GVHD的事件。目的小儿HCT的早期试验是评估剂量，安全性，药代动力学，药效学和 Vorinostat的RP2D。重要的其他端点包括相关实验室研究，认知功能，和患者报告的HRQOL结果。我们假设用伏诺替纳斯特抑制HDAC可以调节 GVHD的炎症反应，并将与保留的认知和HRQOL相关。这项研究将注册儿科HCT患者的出于以下原因：1）精心设计的GVHD非常未满足小儿HCT的临床试验，综合临床结果，生物学功能，认知评估和 HRQOL测量； 2）我们先前对HDAC抑制GVHD预防的临床前和临床数据成人HCT提供了与作用机理相关的生物学相关性； 3）HDAC抑制可能具有神经保护特性并保留同种异体HCT后HRQOL，该治疗已知对负面影响认知功能，尤其是在接受无关供体移植物的患者中，并且可能最重要年轻的患者。这就是该提案将提供有关安全性，耐受性和的关键信息小儿HCT中伏诺替纳斯特的初步效率，以告知未来的全尺度试验。

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

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

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