Hematopoietic Stem Cell Transplant in Patients With Refractory Sarcoidosis: A Phase I/II Trial
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 2
- 主要终点
- Presence of Toxicity
研究概览
简要总结
Sarcoidosis is a disease believed to be due to immune cells, cells which normally protect the body, but are now attacking lungs, heart, nerves, or other organs or systems within the body. As a result, the affected organs or systems fail to work properly causing difficulty breathing; heart failure; inability of the nerves to respond properly causing numbing, tingling, pain, and progressive muscle weakness; or other symptoms depending on the organ or body system involved. The likelihood of progression of this disease is high. This study is designed to examine whether treating patients with high dose cyclophosphamide (a drug which reduces the function of the immune system) and ATG (a protein that kills the immune cells that are thought to be causing this disease), followed by return of the previously collected blood stem cells will stop the progression of sarcoidosis. Stem cells are undeveloped cells that have the capacity to grow into mature blood cells, which normally circulate in the blood stream. The purpose of the high dose cyclophosphamide and ATG is to destroy the cells in the immune system. The purpose of the stem cell infusion is to evaluate whether this treatment will produce a normal immune system that will no longer attack the body.
详细描述
Method of Harvesting Stem Cells
Based on the experience of the pilot studies, the current protocol will mobilize stem cells with granulocyte-colony stimulating factor (G-CSF) and collect stem cells by apheresis, with subsequent bone marrow harvest performed only if needed to supplement the peripheral blood stem cells (PBSC). Based on experience of autoimmune flares in patients receiving G-CSF alone for mobilization, patients will be mobilized with cyclophosphamide 2.0 g/m2 and G-CSF 10 mcg/kg.
Cyclophosphamide
Cyclophosphamide (CY) is an active agent in patients with a wide variety of malignancies. It is used frequently in the therapy of lymphoid malignancies and has potent immunosuppressive activity. It is frequently used as a cytotoxic and immunosuppressive agent in patients undergoing marrow transplants and as a treatment for patients with autoimmune diseases. It is an alkylating agent that requires hepatic metabolism to the active metabolites, phosphoramide mustard and acrolein. These active metabolites react with nucleophilic groups. It is available as an oral or intravenous preparation. Bioavailability is 90% when given orally. The half-life of the parent compound is 5.3 hours in adults, and the half-life of the major metabolite phosphoramide mustard is 8.5 hours. Liver or renal dysfunction will lead to prolonged serum half-life. CY is administered intravenously at a dosage of 60 mg/kg on each of 2 successive days (use adjusted ideal body weight if patient's actual body weight is greater than 100% ideal body weight). The major dose limiting side effect at high doses is cardiac necrosis. Hemorrhagic cystitis can occur and is mediated by the acrolein metabolite. This can be prevented by co-administration of MESNA or bladder irrigation. Other notable side effects include nausea, vomiting, alopecia, myelosuppression and SIADH. Refer to institutional manuals for more information about administration, toxicity and complications.
Rabbit-Derived Anti-Thymocyte Globulin (ATG)
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18years and ≤ 60 years at the time of pretransplant evaluation.
- •Definitive diagnosis of sarcoidosis in pathologic specimen.
- •Patients who failed to respond to conventional treatment of at least 3 months duration with corticosteroids (equivalent dosage of prednisone 1.0mg/kg/day to start). Patients must also have failed two or more of the followings: TNF inhibitors (etanercept, infliximab), methotrexate, azathioprine, 6-MP, cyclosporin, tacrolimus, mycophenolate mofetil, gold, dapsone, colchicine, chloroquine/hydroxychloroquine or any other immunosuppressive or modulating drugs.
- •Failure of therapy defined by (not caused by unrelated conditions) any one of following:
- •Progressive pulmonary disease (stage II or III) defined by decline in pulmonary function (DLCo, VC or FEV1) of 15% or more over 12 months.
- •Progressive CNS disease (worsening symptoms such as paraparesis or medically refractory seizure).
- •Persistent peripheral neuropathy (one of following):
- •Persistent muscle weakness Grade 3/5 or worse (MRC) in at least one movement (e.g. ankle dorsiflexion) in two limbs.
- •Persistent cranial nerve involvement such as persistent facial diplegia.
- •Persistent incapacitating sensory loss (e.g. gait ataxia, falls > 1/month).
- •Progressive loss of vision.
- •Persistent hypercalcemia.
- •Cardiac sarcoidosis that is proven by cardiac biopsy or cardiac MRI.
排除标准
- •Alternative diagnosis.
- •Noncompliance to medical care.
- •> 10 pack-year history of cigarette smoking if lung disease is the major problem.
- •Poor performance (PS) status (ECOG >2) at the time of entry, unless decline of PS is due to the disease itself.
- •Significant end organ damage such as:
- •Overt congestive heart failure (NYHA Class III or IV).
- •Active ischemic heart disease, s/p myocardial infarction within 6 months, s/p unstable angina within 3 months, s/p CVA within 6 months, s/p hospitalization for CHF within 3 months.
- •Untreated life-threatening arrhythmia.
- •Pulmonary hypertension > 40 mmHg.
- •End-stage lung disease (TLC < 55%, FVC < 55%, or DLCO < 40% of predicted value).
- •Serum creatinine > 2.5 or creatinine clearance < 30 ml/min.
- •Liver cirrhosis, transaminases > 3x normal or bilirubin > 2.0 unless due to Gilbert's disease.
- •HIV positive.
- •Uncontrolled diabetes mellitus, or any other illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive treatment.
- •Prior history of malignancy except localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured by local surgical therapy, such as (but not limited to) head and neck cancer, or stage I or II breast cancer will be considered on an individual basis.
- •Positive pregnancy test, inability or unable to pursue effective means of birth control, failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
- •Significant psychological issues, social issues, psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible.
- •Inability to give informed consent.
- •Major hematological abnormalities such as platelet count less than 100,000/ul, ANC less than 1000/ul.
研究组 & 干预措施
Autologous hematopoietic stem cell transplantation
Autologous stem cells will be injected after conditioning
干预措施: Autologous hematopoietic stem cell transplantation (Biological)
Allogeneic stem cell transplantation
Allogeneic stem cells will be injected after conditioning
干预措施: Allogeneic stem cell transplantation (Biological)
结局指标
主要结局
Presence of Toxicity
时间窗: For length of hospital stay (until discharge).
Daily assessment will be made with regards to toxicity by one of the protocol investigators.National Cancer Institute Common Toxicity Criteria will be used to grade all non-hematologic toxicities. Toxicity grades as follows: 1 = Mild; 2 = Moderate; 3 = Severe and undesirable; 4 = life threatening or disabling ; 5 = Death
Survival
时间窗: Participants are to be followed at 6 months and then yearly until 5 years
Patient has not died.
Time to Disease Progression
时间窗: Participants are to be followed at 6 months and then yearly until 5 years
Worsening symptoms, pulmonary function studies, cardiac function and arrhythmia including EKG assessments, and neurological symptoms.
次要结局
未报告次要终点
研究者
Richard Burt, MD
MD
Northwestern University