Hematopoietic Stem Cell Support in Patients With Refractory Sarcoidosis
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT00282438|
Recruitment Status : Terminated (No plan to continue enrollment)
First Posted : January 26, 2006
Results First Posted : February 24, 2017
Last Update Posted : February 24, 2017
|Condition or disease||Intervention/treatment||Phase|
|Sarcoidosis||Biological: Autologous hematopoietic stem cell transplantation Biological: Allogeneic stem cell transplantation||Phase 1 Phase 2|
Hide Detailed Description
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 (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)
Rabbit-derived anti-human thymocyte globulin (ATG) is a gamma globulin preparation obtained from hyperimmune serum of rabbits immunized with human thymocytes. ATG has been used predominately in solid organ transplant immunosuppressive regimens. ATG is a predominantly lymphocyte-specific immunosuppressive agent. It contains antibodies specific to the antigens commonly found on the surface of T cells. After binding to these surface molecules, ATG promotes the depletion of T cells from the circulation through mechanisms, which include opsonization and complement-assisted, antibody-dependent, cell-mediated cytotoxicity. The plasma half-life ranges from 1.5 12 days. ATG is administered intravenously at a dose of 0.5-mg/kg recipient body weight on day -6 and at a dose of 1.0 mg/kg recipient body weight on days -5 to -1. Unlike equine ATG, rabbit ATG does not require a pre-infusion skin test to check for hypersensitivity. Methylprednisolone 250mg (dose adjusted based on patient's condition) will be given before every dose of ATG. Additional medications such as diphenhydramine may be given at the discretion of the attending physician. Although rare, the major toxicity is anaphylaxis; chills, fever, pruritus or serum sickness may occur.
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.
Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion. Consequently, clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as approximately 20 hours. In vitro, plasma protein binding of fludarabine ranged between 19% and 29%.
Campath-1H is a humanized fusion protein that is directed to CD52 antigen that is expressed on all lymphocytes, monocytes and macrophages. It has very potent immunosuppressive property and is effective for prevention of graft-versus-host disease. 30 mg/day of CAMPATH will be given intravenously over 2 hours on days -4, -3 and -2. The most commonly reported adverse reactions are infusion reactions fever, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspnea), cytopenias (neutropenia, lymphopenia, thrombocytopenia, anemia), and infections (CMV viremia, CMV infection, other infections). In clinical trials, the frequency of infusion reactions was highest in the first week of treatment. Other commonly reported adverse reactions include vomiting, abdominal pain, insomnia and anxiety. The most commonly reported serious adverse reactions are cytopenias, infusion reactions, and immunosuppression/infections. About 30 minutes before the patient gets Campath, he/she will be given other medications (such as acetaminophen or diphenhydramine, given orally, not IV) to help reduce side effects.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||2 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Hematopoietic Stem Cell Transplant in Patients With Refractory Sarcoidosis: A Phase I/II Trial|
|Study Start Date :||December 2003|
|Actual Primary Completion Date :||August 2015|
|Actual Study Completion Date :||August 2015|
Experimental: Autologous hematopoietic stem cell transplantation
Autologous stem cells will be injected after conditioning
Biological: Autologous hematopoietic stem cell transplantation
Autologous hematopoietic stem cells will be injected after conditioning
Other Name: Autologous stem cell injection
Experimental: Allogeneic stem cell transplantation
Allogeneic stem cells will be injected after conditioning
Biological: Allogeneic stem cell transplantation
Allogeneic stem cells will be injected after conditioning
- Toxicity [ Time Frame: 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 [ Time Frame: Participants are to be followed at 6 months and then yearly until 5 years ]Patient has not died.
- Time to Disease Progression [ Time Frame: 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.
- Disease Improvement [ Time Frame: 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00282438
|United States, Illinois|
|Northwestern University, Feinberg School of Medicine|
|Chicago, Illinois, United States, 60611|
|Principal Investigator:||Richard Burt, MD||Northwestern University|