Sung Won Choi - US grants

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.

ABSTRACT The candidate, Sung Won Choi MD MS, is a physician-scientist who has developed a career in patient-oriented research (POR). She is an active clinical pediatric oncologist who focuses on treating life-threatening blood diseases with novel immune-based therapies, such as allogeneic hematopoietic cell transplant (HCT). Despite the potentially curative intent of HCT, its broader application has been limited by acute graft-versus host disease (GVHD). Unfortunately, acute GVHD can negatively impact clinical and health-related quality of life (HRQOL) outcomes and lead to substantial morbidity and mortality. Dr. Choi?s research program has focused on designing innovative clinical trials to mitigate acute GVHD by incorporating biological, clinical, and psychosocial correlative studies and leveraging modern mobile health technologies to further enhance care delivery. Thus, her research program provides a unique training opportunity for early stage investigators interested in POR, which is complemented by the following outstanding resources at the University of Michigan: (1) NHLBI T32 Training Grant in Hematology (T32 HL007622); (2) Michigan Institute for Clinical and Health Research (MICHR) | Clinical and Translational Science Award (UL1TR002240); (3) Clinical Trials Support Unit; and (4) School of Public Health. This ideal training environment will allow young, clinical investigators to develop and gain new skills in clinical trials design, qualitative and quantitative research methods, communication and presentation skills, manuscript and grant writing, professional growth, individual development plans, team science projects, ethical conduct of research, and protection of human subjects. Indeed, this rich environment has influenced Dr. Choi?s overall career goal of designing rigorous POR studies, mentoring the next generation of POR investigators, and together with her mentees, making meaningful contributions to the clinical and HRQOL outcomes of family caregivers and HCT patients through joint productive activity. In this application, Dr. Choi proposes didactic courses and group discussions coupled with experiential training in her currently funded research projects: in a phase I/II clinical trial, to test the safety and efficacy of a histone deacetylase (HDAC) inhibitor to prevent acute GVHD in pediatric HCT (Aim 1); in a mobile health randomized trial, to examine the effectiveness of Roadmap 2.0, a positive psychology intervention in family caregivers of HCT patients (Aim 2). Dr. Choi will also develop new research directions by generating preliminary data for a future, full-scale just-in-time adaptive intervention (JITAI) to promote physical and mental HRQOL in family caregivers of HCT patients (Aim 3). This new research direction is a logical extension of Aim 2. Thus, these projects will collectively provide Dr. Choi?s trainees with unique experiences in: i) multidisciplinary team science; ii) designing, conducting, and analyzing pharmaceutical and non-pharmaceutical (social and behavioral) interventions; iii) early phase clinical trial design and randomized controlled trial design; and iii) and generating new research ideas as well as preliminary data for future grant applications. Dr. Choi will expand her mentoring activities and build core knowledge in professional development.