A Pilot Study of Autologous Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide for Children and Young Adults With Refractory Crohn's Disease.
试验速览
- 阶段
- 不适用
- 状态
- 撤回
- 发起方
- 主要终点
- To determine the feasibility and toxicity of immunoablation with HSCT and post-HSCT infusion of cyclophosphamide in children and young adults with refractory Crohn's disease (CD).
研究概览
简要总结
This is a study for people with Crohn's Disease (CD) that are not responsive to standard treatment. CD is a chronic disease with an auto-immune component that goes away and relapses over the years and causes lifelong impairment of health and quality of life. Regardless of the therapy used some patients remain seriously ill with active disease after multiple therapeutic options have been exhausted. There is currently no drug that will cure CD. Drug treatment is focused on controlling symptoms. Another treatment is to perform surgery but again this does not lead to cure and is often linked to infection, short gut syndrome problems and psycho-social and cosmetic issues. Therefore, a treatment that does not involve surgery or long-term drug treatment may be beneficial especially to young adults.
Hematopoietic stem cell transplantation (HSCT) has been of value in other auto-immune diseases and it is possible that it could be of value in CD. This is a pilot study to determine if HSCT is safe and effective for children and young adults with severe CD. For this study the stem cells will come from the patient. This is called an autologous transplant. The patient will undergo collection and storage of his/her peripheral blood stem cells (PBSC). The patient will be given drugs to move (or mobilize) the stem cells from his/her bone marrow into his/her blood where they will be collected on a machine called apheresis (similar to dialysis.) The cells will be stored and given back to the patient about 1 month after collection.
详细描述
Crohn's Disease (CD) is an immunologically mediated chronic illness that has a relapsing and remitting course, most commonly presenting in the 2nd or 3rd decade and causing lifelong impairment of health and quality of life. Mainstay of clinical treatment for severe disease is combination of anti-inflammatory agents like 5-aminosalicyaltes and immunosuppressive medications like corticosteroids and newer anti-TNF antibodies like Infliximab. None of the drugs are, at present, curative and a relevant subset of patients are refractory to many of these pharmacologic approaches.
Immunoablative treatment followed by autologous stem cell rescue (Autologous HSCT) has been tried in this refractory group of patients with successful results. Autologous HSCT is effective in this auto-immune setting through the eradication of effector/memory T-cell clones due to a direct immuno-ablative effect of drugs used in the preparative regimen; by leading to an immune-reset- recovering clones of T- cells from the infused stem cells do not mount an auto- immune response and are tolerant to 'self' antigens and, by upregulation of T regulatory cells (Treg, CD4+CD25+FOXP3+ or CD8+ FOXP3+) via change in cytokine mileu during transplant. Increased population of Tregs restricts the activity of self-reactive effector T-cells.
This pilot study is designed to gain on the success of previously published adult studies of autologous HSCT in refractory CD, with the aim to confirm the feasibility, safety and efficacy of HSCT and post-transplant cyclophosphamide when given post-HSCT in pediatric patients and young adults.
Since, this combination of immuno-ablative therapy with post-transplant cyclophosphamide has not been extensively studied in children with CD, therefore transplant related mortality (TRM) and severe toxicity (> grade 3 toxicity by NCI criteria) will be monitored for 100 days post-transplant in all the patients and stopping rules will be enforced in case of excessive toxicity or TRM (>10%). Clinical assessments will be done for 1 year post-HSCT for disease activity, steroid free remission period to evaluate the 'clinical efficacy' of this procedure.
The major aim of this pilot is to generate the preliminary safety data to confirm the feasibility and benefit of autologous HSCT in children and young adults with refractory CD.
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
- 10 Years 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All the subjects considered eligible for the study will be screened and reviewed by the Gastroenterology (GI) physicians prior to enrollment (Dedrick Moulton, MD or his designee at Vanderbilt Children's Hospital)
- •Age ≥ 10 and < 30 years
- •Disease status:
- •Confirmed diagnosis of Crohn's Disease: Diagnosis of Crohn's disease that has been established based on typical endoscopic/histologic and/or radiological appearances.
- •Active disease, defined as: Pediatric Crohn's Disease Activity Index (PCDAI) >30 (see Appendix I) or Crohn's Disease Activity Index (CDAI) of >250 (see Appendix II) at any time within 3 months prior to enrollment and any one of the following- i. Endoscopic evidence of active disease confirmed on histology within 3 months prior to enrollment, or ii. Clear evidence of active small bowel Crohn's disease on small bowel imaging within 3 months prior to enrollment.
- •Refractory disease- Moderate to severe disease that has been unresponsive to current or prior therapy with mercaptopurine and/or azathioprine (thiopurines), methotrexate and anti-TNF therapy. Patients should have relapsing disease (i.e. ≥ 1 exacerbation/year) or corticosteroid dependence despite current or prior thiopurines, methotrexate and anti-TNF maintenance therapy or clear demonstration of intolerance or toxicity to these drugs. Patients who fail induction therapy with corticosteroids and anti-TNF therapy, and are therefore not eligible to receive maintenance therapy with thiopurines or methotrexate will also be candidates for enrollment.
- •4. Negative stool culture, C. difficile, and negative CMV pcr (in stool or colonic biopsy). Patients with CMV colitis will receive a trial of anti-viral treatment and only responders will be considered eligible for inclusion.
- •5. Patients with a prior ileostomy or colostomy may enter the study. For this group of patients', physician's global assessment will be used to assess clinical activity of CD, as Pediatric CDAI and CDAI scoring method may not be representative of disease activity.
- •6. Patients with abscesses are eligible to enroll once the abscesses or any other significant infection has resolved.
排除标准
- •Pregnancy or unwillingness to use adequate contraception during the study- if a woman is of childbearing age.
- •HIV infection.
- •Organ function criteria-
- •Renal: creatinine clearance < 50 ml/min/1.73m2 (measured or estimated).
- •Cardiac: left ventricular ejection fraction <30% by multigated radionuclide angiography (MUGA) or a shortening fraction of < 25% by cardiac echocardiogram.
- •Pulmonary Function tests: DLCO < 30% or patient on oxygen.
- •Hepatic: serum bilirubin > 3 mg%; AST and ALT > 3x ULN for the institutional lab.
- •Uncontrolled Hypertension (using age based criteria) despite at least 2 anti- hypertensive agents.
- •Active Infection or risk thereof-
- •Current abscess or significant active infection
- •Perianal infection is not an exclusion criterion, provided there is drainage with or without placement of drain.
- •Abnormal chest x- ray (CXR) consistent with active infection or neoplasm.
- •Severe diarrhea due to short small bowel; patients believed to have < 700 mm of small bowel and diarrhea attributable to this will be excluded.
- •Patients with toxic megacolon, active bowel obstruction or intestinal perforation.
- •Unable to collect minimum of 3 x106/kg CD34+ cell dose. These patients will be excluded from receiving the preparative regimen.
结局指标
主要结局
To determine the feasibility and toxicity of immunoablation with HSCT and post-HSCT infusion of cyclophosphamide in children and young adults with refractory Crohn's disease (CD).
时间窗: first 100 days post HSCT
This is a composite outcome to determine the feasibility and toxicity of immunoablation with HSCT and post-HSCT infusion of cyclophosphamide in children and young adults with refractory Crohn's disease (CD). Death (transplant related mortality, TRM) and severe non-hematologic toxicity (≥ grade 3 toxicity; NCI Toxicity Criteria version 4.0) within the first 100 days after HSCT will be monitored to meet this end-point.
次要结局
- 1. Incidence of viral reactivations - CMV and EBV(First 100 days post HSCT)
- 2. Incidence of invasive fungal infections(within first 100 days post HSCT)
- 4. Evaluate the efficacy and benefit of HSCT in this population at 1 year post HSCT, by serial assessments of clinical activity of CD, assessment of disease severity- CDAI scores and length of steroid free remissions.(1 year post transplant)
- 3. Immune reconstitution after HSCT(Until the study is closed which is anticipated to be approximately 3 years.)
研究者
Haydar Frangoul
Medical Director, Pediatric Hematology Oncology
TriStar Health