Ignite Creation Date:
2024-05-05 @ 11:48 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00130754
Status:
COMPLETED
Last Update Posted:
2011-02-23
First Post:
2005-08-15
Brief Title:
Thymoglobuline in Non-myeloablative Allogeneic Stem-cell Transplantation
Sponsor:
Hadassah Medical Organization
Organization:
Hadassah Medical Organization
Study Overview
Official Title:
A Prospective Randomized Controlled Pilot Study in Order to Evaluate the Place of Thymoglobuline in Non-myeloablative Allogeneic Hemapoietic Stem-cell Transplantation NST
Status:
COMPLETED
Status Verified Date:
2007-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Allogeneic stem cell transplantation is the treatment of choice for a growing number of malignant and non-malignant indications Until recently myeloablative in conjunction with immunosuppressive conditioning was considered mandatory for the elimination of malignant hematopoietic cells and to prevent graft rejection The aim of allogeneic non-myeloablative stem cell transplantation NST is to induce host-to-graft tolerance with fast and durable engraftment of donor stem cells by means of conditioning which is well-tolerated by patients The rationale behind the NST strategy is to induce optimal graft-versus-leukemia GVL effects for the elimination of all malignant cells by alloreactive immunocompetent cells from a matched donor as an alternative to standard high-dose myeloablative chemo radiotherapy The NST protocol is therefore mainly based on immunosuppression and thus contains fludarabine low dose busulfan and anti-T-lymphocyte globulin ATG Thymoglobuline is a polyclonal rabbit antiserum specific for human T cells used in organ transplantation for induction of tolerance and rejection prevention and treatment It was also used in stem-cell transplantation SCT for the same purposes eg for generation of tolerance and rejection preclusion as well as a treatment for graft-versus-host disease GVHD Data from myeloablative protocols suggest that ATG before SCT significantly reduces the risk for grade III-IV acute GVHD This does not translate to a reduction in transplant-related mortality TRM because of the increased risk for infections and thus survival is unchanged Extensive chronic GVHD was also significantly shown to be reduced in patients receiving ATG in the myeloablative setting However the role of ATG in the NST protocol was never evaluated in a prospective randomized trial In view of the preliminary data suggesting of an additive effect of ATG in these circumstances we the investigators at Hadassah Medical Organization evaluate the effect of ATG in NST by a prospective randomized trial
Detailed Description:
Allogeneic stem cell transplantation SCT from a fully matched donor is the treatment of choice for a growing number of malignant and non-malignant indications Until recently myeloablative in conjunction with immunosuppressive conditioning was considered mandatory for the elimination of malignant hematopoietic cells and to prevent graft rejection The aim of allogeneic non-myeloablative stem cell transplantation NST is to induce host-to-graft tolerance with fast and durable engraftment of donor stem cells by means of conditioning which is well-tolerated by patients The rationale behind the NST strategy is to induce optimal graft-versus-leukemia GVL effects for the elimination of all malignant cells by alloreactive immunocompetent cells from a matched donor as an alternative to standard high-dose myeloablative chemo radiotherapy The NST protocol is therefore mainly based on immunosuppression and thus contains fludarabine low dose busulfan and anti-T-lymphocyte globulin ATG Thymoglobuline is a polyclonal rabbit antiserum specific for human T cells used in organ transplantation for induction of tolerance and rejection prevention and treatment It was also used in SCT for the same purposes eg for generation of tolerance and rejection preclusion as well as a treatment for GVHD Data from myeloablative protocols suggest that ATG before SCT significantly reduces the risk for grade III-IV acute GVHD This does not translate to a reduction in TRM because of the increased risk for infections and thus survival is unchanged Extensive chronic GVHD was also significantly shown to be reduced in patients receiving ATG in the myeloablative setting However the role of ATG in the NST protocol was never evaluated in a prospective randomized trial In view of the preliminary data suggesting of an additive effect of ATG in these circumstances we propose the following clinical trial
Objectives To evaluate the effect of ATG vs no ATG on the incidence of GVHD in patients undergoing NST
Study parameters
Primary end points -
Acute GVHD occurrence
Acute GVHD grading
Secondary end points -
Time to acute GVHD
Chronic GVHD occurrence
Chronic GVHD grading
Engraftmentgraft rejection
Overall survival
Disease free survival
Infections
Transplant-related mortality TRM
Transplant-related toxicity TRT
Treatment schedule
30 patients with fully matched donors will be included Patients will be randomized for two groups
Patients who will get rabbit anti-human T lymphocyte globulin thymoglobuline R SangStat as a part of pre-transplant conditioning
Patients who will not get rabbit anti-human T lymphocyte globulin thymoglobuline R SangStat as a part of pre-transplant conditioning
Randomization
Randomization will be done by GENZYME Israel Ltd The center will send a randomization form to GENZYME Israel by fax and the company will fax back the randomization status of the patient Randomization will be preformed up to day -10 pre-transplant
Inclusion criteria
Patients ages 18-75 years old with a disease necessitating allogeneic SCT
Patients must have an HLA compatible donor willing and capable of donating peripheral blood stem cells preferably or bone marrow progenitor cells using conventional techniques and lymphocytes if indicated HLA compatible defined as 56 or 66 matched related A B DR or 88 molecular A B C DR matched unrelated donor
Both patients and donor must sign written informed consents
Patients must have an ECOG PS 2 Creatinine 20 mgdl Ejection fraction 40 DLCO 50 of predicted Serum bilirubin 3 gmdl elevated GPT or GOT 3 x normal values
Exclusion criteria
Not fulfilling any of the inclusion criteria
Active life-threatening infection
Overt untreated infection
Hypersensitivity to thymoglobuline or other rabbit produced immunoglobulin
HIV seropositivity hepatitis B or C antigen positivity with active hepatitis
Pregnant or lactating women
Donor contraindication HIV seropositive confirmed by Western Blot hepatitis B antigenemia evidence of bone marrow disease unable to donate bone marrow or peripheral blood due to concurrent medical condition
Inability to comply with study requirements
CONDITIONING PROTOCOL
All patients will be prepared by the NST protocol IVfludarabine 30mgm2day on days -10 to -5 and oral busulfan 4mgkg in 4 divided daily doses on days -6 and -5 or IV Busulfex a dose of 32 mgkg on days -6 and -5with or without IV ATG according to randomization group on days -4 to -1 ATG dosing schedule a cumulative dose of 75 mgkg ATG will be given with the following program - 05 mgkg day -4 20 mgkg day -3 25 mgkg day -2 25 mgkg day -1 Each days infusion time will be 8 hours The last dose on day -1 should be given within 24 hours pre the stem cell infusion
Prior to NST all patients will receive trimethoprimsulfamethoxazole 10 mgkgd trimethoprim in days -10 to -2 acyclovir 500 mgm2 x 3day from days -6 until day 100 and allopurinol 300 mgday on days -10 to -1 Administration of trimethoprimsulfamethoxazole twice weekly will be reinstituted after recovery from neutropenia as a preventive measure against pneumocystis carinii infection Starting on day -8 patients are monitored with a pp65 antigenemiaCMV PCR on a weekly basis to detect cytomegalovirus CMV Two consecutive positive PCR results or one antigenemia with more then one cell positive for pp65 serve as an indication for replacing acyclovir with ganciclovir 10 mgkgday until minimum of two negative tests are obtained
Neutropenic patients with culture-negative fever receive a combination of gentamicin cefazolin and piperacillin as a first line antibiotic protocol Persisting fever are treated with amikacin and tazocin as a second line protocol while meropenem and vancomycin are used as the third line protocol In cases of persistent fever not responding to antibiotic therapy within 5 days amphotericin B 07 mgkgd is added until the neutropenia resolves No antifungal prophylaxis will be given
Graft-vs-host disease GVHD prophylaxis consisting of single-drug low-dose short- term cyclosporine- A CSP 3 mgkg iv daily in two divided doses starting on day -4 Once the patients are mobile CSP will be administered orally CSP dosage will be tapered during the second or third month post transplant according to chimeric status and evidence of GVHD and then gradually stopped unless the patient will develop GVHD or graft failure Immediately upon the appearance of signs and symptoms of GVHD iv methylprednisolone 2 mgkg and CSP will be administered
PBSC donors will be injected subcutaneously with granulocyte-colony stimulating factor G-Neupogen 5 mgkg twice daily for 5 days and mobilized peripheral blood stem cells will be collected on days 5 and 6
Definitions
Engraftment
The 1st day of PBSC infusion is designated as day 0 Engraftment is defined as ANC05x109L and peripheral WBC1x109L for 3 consecutive days and unsupported platelets25x109L
Chimerism
Chimerism will be assessed by standard cytogenetic analysis in malefemale donor-recipient Residual male cells in female chimera will be detected by amelogenine gene method In sex-matched donor-recipient combinations the various number of tandem repeats VNTR polymerase chain reaction PCR with a 5 sensitivity of detection will be used to assess the presence of residual host or donor cells
Graft versus host disease GVHD
Acute and chronic GVHD will be graded according to the International Stem Cell Transplantation Registry ISCTR severity index
Graft rejection
Graft rejection is defined as peripheral blood aplasia and marrow hypoplasia 21 days post-transplant with no evidence of donor markers revealed by cytogenetic and molecular techniques
Transplant-related mortality TRM
TRM is defined as mortality occurring due to the transplant procedure with the patient in complete remission from the beginning of conditioning to day 100
Transplant-related toxicity TRT
All nonhematological toxicities including multi-organ dysfunction from day 0 to 100 are considered as regimen-related toxicity and graded according to the criteria of Bearman et al
Time of follow-up study will be ended 1-year post transplant
Objectives To evaluate the effect of ATG vs no ATG on the incidence of GVHD in patients undergoing NST
Study parameters
Primary end points -
Acute GVHD occurrence
Acute GVHD grading
Secondary end points -
Time to acute GVHD
Chronic GVHD occurrence
Chronic GVHD grading
Engraftmentgraft rejection
Overall survival
Disease free survival
Infections
Transplant-related mortality TRM
Transplant-related toxicity TRT
Treatment schedule
30 patients with fully matched donors will be included Patients will be randomized for two groups
Patients who will get rabbit anti-human T lymphocyte globulin thymoglobuline R SangStat as a part of pre-transplant conditioning
Patients who will not get rabbit anti-human T lymphocyte globulin thymoglobuline R SangStat as a part of pre-transplant conditioning
Randomization
Randomization will be done by GENZYME Israel Ltd The center will send a randomization form to GENZYME Israel by fax and the company will fax back the randomization status of the patient Randomization will be preformed up to day -10 pre-transplant
Inclusion criteria
Patients ages 18-75 years old with a disease necessitating allogeneic SCT
Patients must have an HLA compatible donor willing and capable of donating peripheral blood stem cells preferably or bone marrow progenitor cells using conventional techniques and lymphocytes if indicated HLA compatible defined as 56 or 66 matched related A B DR or 88 molecular A B C DR matched unrelated donor
Both patients and donor must sign written informed consents
Patients must have an ECOG PS 2 Creatinine 20 mgdl Ejection fraction 40 DLCO 50 of predicted Serum bilirubin 3 gmdl elevated GPT or GOT 3 x normal values
Exclusion criteria
Not fulfilling any of the inclusion criteria
Active life-threatening infection
Overt untreated infection
Hypersensitivity to thymoglobuline or other rabbit produced immunoglobulin
HIV seropositivity hepatitis B or C antigen positivity with active hepatitis
Pregnant or lactating women
Donor contraindication HIV seropositive confirmed by Western Blot hepatitis B antigenemia evidence of bone marrow disease unable to donate bone marrow or peripheral blood due to concurrent medical condition
Inability to comply with study requirements
CONDITIONING PROTOCOL
All patients will be prepared by the NST protocol IVfludarabine 30mgm2day on days -10 to -5 and oral busulfan 4mgkg in 4 divided daily doses on days -6 and -5 or IV Busulfex a dose of 32 mgkg on days -6 and -5with or without IV ATG according to randomization group on days -4 to -1 ATG dosing schedule a cumulative dose of 75 mgkg ATG will be given with the following program - 05 mgkg day -4 20 mgkg day -3 25 mgkg day -2 25 mgkg day -1 Each days infusion time will be 8 hours The last dose on day -1 should be given within 24 hours pre the stem cell infusion
Prior to NST all patients will receive trimethoprimsulfamethoxazole 10 mgkgd trimethoprim in days -10 to -2 acyclovir 500 mgm2 x 3day from days -6 until day 100 and allopurinol 300 mgday on days -10 to -1 Administration of trimethoprimsulfamethoxazole twice weekly will be reinstituted after recovery from neutropenia as a preventive measure against pneumocystis carinii infection Starting on day -8 patients are monitored with a pp65 antigenemiaCMV PCR on a weekly basis to detect cytomegalovirus CMV Two consecutive positive PCR results or one antigenemia with more then one cell positive for pp65 serve as an indication for replacing acyclovir with ganciclovir 10 mgkgday until minimum of two negative tests are obtained
Neutropenic patients with culture-negative fever receive a combination of gentamicin cefazolin and piperacillin as a first line antibiotic protocol Persisting fever are treated with amikacin and tazocin as a second line protocol while meropenem and vancomycin are used as the third line protocol In cases of persistent fever not responding to antibiotic therapy within 5 days amphotericin B 07 mgkgd is added until the neutropenia resolves No antifungal prophylaxis will be given
Graft-vs-host disease GVHD prophylaxis consisting of single-drug low-dose short- term cyclosporine- A CSP 3 mgkg iv daily in two divided doses starting on day -4 Once the patients are mobile CSP will be administered orally CSP dosage will be tapered during the second or third month post transplant according to chimeric status and evidence of GVHD and then gradually stopped unless the patient will develop GVHD or graft failure Immediately upon the appearance of signs and symptoms of GVHD iv methylprednisolone 2 mgkg and CSP will be administered
PBSC donors will be injected subcutaneously with granulocyte-colony stimulating factor G-Neupogen 5 mgkg twice daily for 5 days and mobilized peripheral blood stem cells will be collected on days 5 and 6
Definitions
Engraftment
The 1st day of PBSC infusion is designated as day 0 Engraftment is defined as ANC05x109L and peripheral WBC1x109L for 3 consecutive days and unsupported platelets25x109L
Chimerism
Chimerism will be assessed by standard cytogenetic analysis in malefemale donor-recipient Residual male cells in female chimera will be detected by amelogenine gene method In sex-matched donor-recipient combinations the various number of tandem repeats VNTR polymerase chain reaction PCR with a 5 sensitivity of detection will be used to assess the presence of residual host or donor cells
Graft versus host disease GVHD
Acute and chronic GVHD will be graded according to the International Stem Cell Transplantation Registry ISCTR severity index
Graft rejection
Graft rejection is defined as peripheral blood aplasia and marrow hypoplasia 21 days post-transplant with no evidence of donor markers revealed by cytogenetic and molecular techniques
Transplant-related mortality TRM
TRM is defined as mortality occurring due to the transplant procedure with the patient in complete remission from the beginning of conditioning to day 100
Transplant-related toxicity TRT
All nonhematological toxicities including multi-organ dysfunction from day 0 to 100 are considered as regimen-related toxicity and graded according to the criteria of Bearman et al
Time of follow-up study will be ended 1-year post transplant
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