Use of Vorinostat as GVHD Prophylaxis in Children, Adolescents, and Young Adults With Non-Malignant Disorders Undergoing Allogeneic Blood and Marrow Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 55
- 试验地点
- 1
- 主要终点
- GVHD-free relapse-free Survival
研究概览
简要总结
This is a single-arm, open label, phase 2 study to determine the safety and efficacy of vorinostat without serotherapy as GVHD prophylaxis when combined with either tacrolimus and methotrexate or post-transplant cyclophosphamide, tacrolimus, and mycophenolate in patients aged 1 to 26 years of age with non-malignant disorders undergoing bone marrow transplant following myeloablative conditioning.
详细描述
The Hypothesis of the trial:
The addition of vorinostat to standard GVHD prophylaxis without serotherapy will lead to improved GVHD-free event-free survival (GEFS) at 1-year post-transplant compared to historical serotherapy-containing GVHD prophylaxis regimens in patients with non-malignant disorders (NMD) undergoing Hematopoietic stem cell transplant (HSCT).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 26 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Non-malignant condition amenable to transplantation, including but not limited to:
- •Primary Immunodeficiency/Primary Immune regulatory disorders
- •Inborn errors of metabolism
- •Red blood cell disorders including hemoglobinopathies per protocol.
- •Inherited bone marrow failure syndromes
- •Available donor per protocol (matched siblings and matched unrelated donors, haploidentical donors). The use of mismatched unrelated donors will not be allowed for this study.
- •Patient and/or legal guardian have signed the informed consent document
- •Adequate organ function and performance status for allogeneic hematopoietic stem cell transplantation as defined by institutional practice:
- •Pulmonary Function: diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in the first second (FEV1), Forced vital capacity (FVC) ≥50% predicted.
- •Renal Function: Estimated or actual glomerular filtration rate (GFR) of ≥50 milliliters per minute (mL/min)/1.72 square meter (m2)
- •Liver Function: aspartate aminotransferase (AST), alanine aminotransferase (ALT) <3x upper limit of normal; total bilirubin ≤2.5 milligrams per deciliter (mg/dL) unless related to disease or Gilbert syndrome. There is no upper limit for bilirubin in patients with confirmed Gilbert syndrome.
- •Cardiac Function: Ejection fraction (EF) ≥50% or fractional shortening (FS) ≥26%
- •Performance Status: Karnofsky/Lansky score ≥70%(HIV) and Human T-lymphotropic virus type (HTLV) I/II negative
- •Infectious Disease testing: human immunodeficiency virus
- •Patients with transfusion-dependent anemias (per protocol) should have a liver MRI to document hepatic iron content (certain values will be excluded)
- •All patients of childbearing age must agree to practice 2 effective methods of contraception at the same time or agree to abstinence for 6 months after the last dose for females. Males with female sexual partners of reproductive potential should use contraception during treatment and for at least 3 months after the last dose.
- •Patients treated with other investigational therapies for underlying disorder must discontinue these therapies prior to enrollment on the study unless, in the opinion of the treating physician, discontinuing these therapies prior to transplant would place the patient at undue risk of morbidity or mortality. In this case, patients must discontinue investigational therapies prior to initiation of the conditioning regimen.
排除标准
- •- Previous diagnosis of Fanconi anemia, dyskeratosis congenita or other telomere biology disorders, inherited genetic conditions known to adversely affect DNA-repair, or other disorders with known chemo- or radiosensitivity.
- •Additional testing may be conducted per investigator discretion but is not required for enrollment.
- •Diagnosis of idiopathic severe aplastic anemia
- •Diagnosis of severe combined immunodeficiency syndrome
- •Diagnosis of malignancy within the last 5 years.
- •Diagnosis of Epstein-Barr virus (EBV)-driven lymphoproliferative disorder within the last 5 years
- •Uncontrolled bacterial, viral, or fungal infection at the time of enrollment
- •Seropositive for HIV or HTLV
- •Active hepatitis B or C
- •Female patients that are pregnant or breast-feeding
- •Inability to take oral medications.
- •History of allergy to Vorinostat, related compounds, or any drugs used as part of the conditioning regimen or GVHD prophylaxis.
- •Patients with transfusion-dependent anemia (≥8 packed red blood cell (PRBC) transfusions/year or ≥20 lifetime transfusions) that have a liver iron content of >8 milligram (mg) Iron(Fe)/Gram dry weight or evidence of bridging fibrosis or cirrhosis on biopsy.
- •Patients enrolled on another GVHD-prevention clinical trial.
- •Patients receiving an ex-vivo T cell-depleted or cluster of differentiation (CD34)-selected stem cell graft.
- •Subjects that have had prior treatment with a histone deacetylase inhibitor (e.g. vorinostat, valproic acid) within the last 30 days.
- •History of prolonged corrected QT interval (QTc) syndrome.
- •Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
研究组 & 干预措施
Vorinostat
For matched sibling and matched unrelated donor transplant recipients Vorinostat will be given orally from day -10 to day 30 post-transplant.
For Haploidentical donor transplant recipients Vorinostat will be given orally from day +5 (at least 24 hours after completion of the day +4 cyclophosphamide) through day 30 post-transplant.
This will be given by liquid suspension or capsule by mouth.
干预措施: Vorinostat (Drug)
结局指标
主要结局
GVHD-free relapse-free Survival
时间窗: 1 year
Composite endpoint of 1-year GVHD-free, event free survival (GEFS) with the addition of vorinostat to standard serotherapy-free GVHD prophylaxis. Grade III-IV acute GVHD and chronic GVHD requiring immunosuppression will be considered in this assessment. Events contributing to this endpoint will include death due to any cause, primary or secondary graft failure/rejection, or second HSCT, whichever occurs first.
Primary graft failure/rejection
时间窗: By day+42 post-Hematopoietic stem cell transplant
Defined as never achieving an absolute neutrophil count (ANC) ≥500/microliters (µL) or never achieving ≥5% donor myeloid chimerism assessed by peripheral blood chimerism assays by day +42 post-Hematopoietic stem cell transplant (HSCT). Second infusion of hematopoietic stem cells is also considered indicative of primary graft failure by day +42 post-HSCT.
Secondary graft failure/rejection
时间窗: Beyond day +42 post-HSCT
Defined as \<5% donor myeloid chimerism in peripheral blood beyond day +42 post-HSCT in patients with prior documentation of hematopoietic recovery with ≥5% donor cells by day +42 post-HSCT.
Secondary graft failure/rejection
时间窗: By day +42 post-HSCT
Second infusion of hematopoietic stem cells is also considered indicative of primary graft failure by day +42 post-HSCT
次要结局
- Overall survival (OS) at day 100, 6-months, and 1-year post-HSCT(Day 100, 6-months, and 1-year post-HSCT)
- Event Free Survival (EFS) at 1-year post-HSCT(1 year post-HSCT)
- Neutrophil engraftment at day 42(Day 42 post-HSCT)
- Platelet engraftment at day 100 post-HSCT(Day 100 post-HSCT)
- Donor chimerism at day 28, 100, and 1-year post-HSCT(Day 28, 100, and 1-year post-HSCT)
- Primary graft failure at day 42(Day 42 post-HSCT)
- Secondary graft failure post-HSCT(Day 42 post-HSCT)
- Day 100 grade II-IV and grade III-IV GVHD(Day 100 post-HSCT)
- Chronic GVHD requiring immunosuppressive therapy (IST) at 1-year post-HSCT(1-year post-HSCT)
- Incidence of grade 4 systemic infections (septicemia) at 1-year post-HSCT(1-year post-HSCT)
- Incidence of viral reactivation by 1-year post-HSCT(1 year post-HSCT)
研究者
Sung Won Choi
Professor of Pediatrics
University of Michigan