Interferon γ-Primed Mesenchymal Stromal Cells as Prophylaxis for Acute Graft v Host Disease After Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Malignancies and Myelodysplasia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 4
- 试验地点
- 3
- 主要终点
- Number of successful preparations and deliveries of investigational product
研究概览
简要总结
The protocol is a phase I open label study evaluating the safety and feasibility of peri-transplant infusion of freshly expanded interferon gamma primed MSCs in adult and pediatric patients undergoing HCT for acute leukemia and myelodysplastic syndrome (MDS).
详细描述
Hematopoietic cell transplantation (HCT) is an established therapeutic modality for high risk hematological malignancies in adults and children. The primary cause of morbidity and mortality after HCT is graft versus host disease (GVHD), affecting up to 70% of patients even with current prophylaxis and directly accounting for approximately a third of regimen-related death. Currently, pharmacologic prophylaxis consists of a calcineurin inhibitor and methotrexate, a drug combination introduced around 40 years ago. Despite this regimen being recognized as the standard of care, it is only partially effective, increases the risk of infection and disease relapse and imparts drug-related, short- and long-term adverse effects. Mesenchymal stromal cells (MSCs) have potent immune modulatory activity which is markedly enhanced by exposure to interferon γ. In murine models, interferon γ (IFNγ) primed MSCs (γMSCs) potently suppress GVHD without untoward adverse effects suggesting this cell therapy may markedly reduce the regimen related toxicity of HCT; however γMSCs have never been infused into patients.
This protocol is designed to test the hypothesis that freshly expanded γMSCs can be reliably produced and safely infused into patients undergoing HCT as GVHD prophylaxis.
This is an investigator-initiated Phase I study using a rolling 6, dose escalation design with two independently accruing expansion cohorts: adults and pediatrics. Accrual to the pediatric tier will commence after the maximum tolerated dose (MTD) has been determined in adults. A successful outcome of this study will lay the foundation for a future Phase II study to demonstrate efficacy and support a Phase III randomized trial.
The researchers plan to enroll a minimum of 4 and maximum of 45 subjects who are greater than 1 year old. Participants will be followed for up to 2 years after the HCT. The study will be conducted at Emory University and will recruit participants from the Winship Cancer Institute and Children's Hospital in Atlanta at Egleston.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All transplant patients who undergo HCT with a myeloablative (MA) or Fludarabine/Melphalan (RIC) conditioning regimen and a HLA A- B- C- DR-matched unrelated donor as treatment for hematologic malignancy or MDS.
- •Age ≥ 1 year at the time that the informed consent document is signed.
- •Patients with acute leukemia must be in complete remission (defined as an M1 marrow -<5% blasts- no evidence of extramedullary disease. Complete remissions without platelet recovery (CRp) will be considered remissions.
- •Planned GVHD prophylaxis with a calcineurin inhibitor and methotrexate per institutional standards.
- •Subject or parent/guardian must sign an informed consent document, and if appropriate, children must sign an assent document.
排除标准
- •Patients who are to receive a non-myeloablative conditioning regimen.
- •Patients receiving another investigational drug for acute GVHD prevention during the conditioning regimen or a planned investigational drug for the first year after transplant (there are no restrictions on GVHD treatment).
- •Any medical or psychological condition or situation deemed by the Investigators to put the patient at increased risk of complications or non-compliance.
- •Patient with a secondary malignancy who would be otherwise eligible for study, but for whom remission from the primary disease cannot be conclusively confirmed or for whom the chance of relapse of the primary disease is significant.
- •Pregnancy (positive serum b-HCG) or breastfeeding.
- •Estimated glomerular filtration rate (GFR) of < 50 mL/min/1.73m
- •Cardiac ejection fraction < 50 (using M-Mode if assessment is done by Echocardiogram)
- •T bilirubin > 2 × upper limit of normal or alanine aminotransferase (ALT) > 4 × upper limit of normal or aspartate aminotransferase (AST) > 4 x upper limit of normal unresolved veno-occlusive disease
- •Pulmonary disease with forced vital capacity (FVC), forced expiratory volume (FEV1) or diffusing capacity for carbon monoxide (DLCO) parameters <45% predicted (corrected for hemoglobin) or requiring supplemental oxygen. Children who are developmentally unable to perform pulmonary function testing will be assessed solely on their need for supplemental oxygen.
- •Karnofsky performance score or Lansky Play-Performance Scale score <80
- •Human leukocyte antigen (HLA) antibody screen positive for HLA antibodies specific against the MSC products.
研究组 & 干预措施
Adult Population
Study participants aged 18 or older who are having an allogeneic blood and marrow transplant (BMT), to treat leukemia, lymphoma or other cancer of the blood will receive an infusion of mesenchymal stromal cells (MSCs).
干预措施: Interferon gamma (IFNγ)-primed human bone marrow-derived mesenchymal stromal cells (Drug)
Pediatric Population
Study participants under 18 years of age who are having an allogeneic blood and marrow transplant (BMT), to treat leukemia, lymphoma or other cancer of the blood will receive an infusion of mesenchymal stromal cells (MSCs).
干预措施: Interferon gamma (IFNγ)-primed human bone marrow-derived mesenchymal stromal cells (Drug)
结局指标
主要结局
Number of successful preparations and deliveries of investigational product
时间窗: Day 1 (day of infusion)
Feasibility will be documented by successful γMSC preparation and delivery to the bedside. If an adverse event precludes initiation or completion of the infusion, this MSC preparation/infusion will, nonetheless, be considered feasible. Processing scored as a not feasible will consist of a cell preparation does not meet release criteria.
Number of adverse events attributed to the investigational product
时间窗: Day 2 (day after infusion)
Safety will be assessed by toxicity grading according to the Common Terminology Criteria for Adverse Events, version 4 (CTCAEv4). All recorded adverse events and serious adverse events will be documented and recorded. Their attribution to γMSCs will be determined. Dose limiting toxicity definition: For this study, dose limiting toxicities (DLTs) will be defined as any grade ≥3 adverse reaction AND attributable to γMSCs (attribution listed as at least probable), occurring from γMSC infusion through the day of hematopoietic engraftment or 21 days of transplant, whichever is later.
Maximal Tolerated Dose
时间窗: Day 2 (day after infusion)
The maximal tolerated dose will be the dose at which 0 of 3 or 1 of 6 subjects demonstrates a DLT. If a dose of 10 x 106 γMSCs/kg is determined to be safe, then we will not determine the true MTD and accept 10 x 106 γMSCs/kg as the maximal dose.
次要结局
- Primary graft failure(Up to Year 2)
- Secondary graft failure(Up to Year 2)
- Platelet engraftment(Up to Year 2)
- Non-relapse mortality (NRM)(Up to Year 2)
- Change in Acute graft-versus-host disease (aGvHD) Incidence(Day 30, Day 100)
- Change in Chronic graft-versus-host disease (cGvHD) Incidence(Day 30, Day 100, Day 180, Day 365)
- Disease-free survival (DFS)(Up to Year 2)
- Primary cause of death(Up to Year 2)
- Relapse(Up to Year 2)
- Early discontinuation(Up to Year 2)
- Viral activation(Up to Day 100)
研究者
Edwin Horwitz
Professor
Emory University