Ignite Creation Date:
2024-05-05 @ 4:39 PM
Last Modification Date:
2024-10-26 @ 9:22 AM
Study NCT ID:
NCT00282438
Status:
TERMINATED
Last Update Posted:
2018-08-31
First Post:
2006-01-24
Brief Title:
Hematopoietic Stem Cell Support in Patients With Refractory Sarcoidosis
Sponsor:
Northwestern University
Organization:
Northwestern University
Study Overview
Official Title:
Hematopoietic Stem Cell Transplant in Patients With Refractory Sarcoidosis A Phase III Trial
Status:
TERMINATED
Status Verified Date:
2018-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
No plan to continue enrollment
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
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 20 gm2 and G-CSF 10 mcgkg
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 53 hours in adults and the half-life of the major metabolite phosphoramide mustard is 85 hours Liver or renal dysfunction will lead to prolonged serum half-life CY is administered intravenously at a dosage of 60 mgkg on each of 2 successive days use adjusted ideal body weight if patients 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 15 12 days ATG is administered intravenously at a dose of 05-mgkg recipient body weight on day -6 and at a dose of 10 mgkg 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 patients 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
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-AMPm2 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
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 mgday 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 immunosuppressioninfections About 30 minutes before the patient gets Campath heshe will be given other medications such as acetaminophen or diphenhydramine given orally not IV to help reduce side effects
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 20 gm2 and G-CSF 10 mcgkg
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 53 hours in adults and the half-life of the major metabolite phosphoramide mustard is 85 hours Liver or renal dysfunction will lead to prolonged serum half-life CY is administered intravenously at a dosage of 60 mgkg on each of 2 successive days use adjusted ideal body weight if patients 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 15 12 days ATG is administered intravenously at a dose of 05-mgkg recipient body weight on day -6 and at a dose of 10 mgkg 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 patients 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
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-AMPm2 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
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 mgday 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 immunosuppressioninfections About 30 minutes before the patient gets Campath heshe will be given other medications such as acetaminophen or diphenhydramine given orally not IV to help reduce side effects
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None