BMT and High Dose Post-Transplant Cyclophosphamide for Chimerism Induction and Renal Allograft Tolerance

Study Overview
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Brief Summary
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The primary objective of this study is to assess the ability of bone marrow transplantation (BMT) and high-dose post-transplantation cyclophosphamide (PT/Cy) to induce renal allograft tolerance and thus enable discontinuation of immunosuppressive therapy in haploidentical living related donor renal transplant recipients.

Detailed Description
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Transplantation is a good treatment for people with end-stage kidney disease. However, there is still much to learn about how to best care for the transplanted kidney and keep it working for a long time. Unless a person receiving a kidney from someone else takes drugs that reduce immune function, the kidney will be rejected. Those drugs must be continued life-long and cause many issues. Therefore, tolerance of the transplanted kidney, without chronic rejection and without the need for permanent immunosuppressive drug treatment, is a highly desirable goal. If this can be achieved, it would make one kidney for life possible. The study treatment includes several days of study medications followed by a kidney and bone marrow transplant. After the transplant, the study treatment will continue with a few more doses of study medications and then anti-rejection medication is started. After a while, the anti-rejection medication is slowly stopped. Researchers will examine blood and tissue samples and try to identify genetic markers for certain conditions like chimerism, response to therapy, and tolerance. *** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.

Official Title
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Bone Marrow Transplantation and High Dose Post-Transplant Cyclophosphamide for Chimerism Induction and Renal Allograft Tolerance (ITN054ST)

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Biological: anti-thymocyte globulin
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Radiation: Total Body Irradiation
* Drug: acetaminophen
* Drug: diphenhydramine
* Drug: methylprednisolone
* Biological: bone marrow transplant
* Drug: MESNA
* Drug: mycophenolate mofetil
* Drug: prednisone
* Drug: filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipient participants must meet all of the following criteria to be eligible for this study: Recipient of a first renal allograft from an Human Leukocyte Antigen (HLA)-haploidentical, living related donor. The donor and recipient must be HLA identical for at least one allele (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype. Age 18 to 65 years. Single solid organ recipients (kidney only). Blood Group System (ABO) compatibility with donor. Donor-Specific Antibody (DSA) will be assessed by the local laboratory 30 days or less prior to transplant using solid phase micro particle technology (by Luminex® phenotype panel or Luminex single antigen bead test.) The following criteria apply: Participants without detectable DSA will be deemed eligible if they meet other entry criteria. Participants with detectable DSA and a positive flow cytometric crossmatch may undergo de-sensitization per standard of care if they are cytotoxic crossmatch negative. Such participants must demonstrate a negative flow cytometric crossmatch by day -9 in order to receive the first dose of study therapy (ATG). Participants who do not demonstrate an acceptable response to de-sensitization by day -9 will be considered screen failures and will be terminated from the study. Participants with a positive cytotoxicity crossmatch will be excluded. No known history of anti-HLA antibodies. Recipients with low- level anti-HLA antibodies not considered to be clinically significant may be eligible, following consultation with the Protocol Chairs, the local HLA Laboratory Director, the NIAID Medical Monitor and the ITN Clinical Trial Physician. Negative T and B cell flow crossmatches with the designated donor; as assessed by local laboratories. If one or more of the crossmatches is positive, the participant will be considered a screen failure unless combined results of antibody and cross match testing implicate a non-HLA antibody as the cause of the positive flow crossmatch. In this case, the Protocol Chair must approve the participant as a screening success after consultation with the local HLA Laboratory Director. Normal estimated left ventricular ejection fraction and no history of ischemic heart disease requiring revascularization, unless cleared by a cardiologist. Forced expiratory volume (FEV1) and forced vital capacity (FVC) > 40% of predicted at the screening visit. Serological evidence of prior Epstein-Barr virus (EBV) infection as documented by positive IgG and negative IgM antibodies against EBV. For women of childbearing potential, a negative serum or urine pregnancy test with sensitivity less than 50 Milli-International unit (mIU)/m within 72 hours before the start of study medication. Use of two forms of contraception with less than a 5% failure rate or abstinence by all transplanted participants for 18 months after the first dose of study therapy. For the first 60 days post-transplant, recipients should be encouraged to use non-hormonal contraceptives due to the potential adverse effect of hormones on bone marrow engraftment. Ability to receive oral medication. Ability to understand and provide informed consent. All participants must demonstrate a negative QuantiFERON® (QFT) assay result within 52 weeks of transplant regardless of Purified Protein Derivative (PPD) status. Participants with a positive QFT assay will not be eligible for the study unless they have completed treatment for latent TB and have a negative chest x-ray. QFT testing done within 52 weeks before transplant is acceptable as long as there is documentation of the results. Prior recipients of a Bacillus Calmette-Guérin (BCG) vaccination are not exempt. Donor participants must meet all of the following criteria to be eligible for this study: HLA-haploidentical, first-degree relatives or half-siblings of the recipient participant at the allele or allele group. The donor and recipient must be HLA identical for at least one allele (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype. Age 18 to 65 years. Creatinine clearance >80 ml/minute as measured from a 24 hour urine collection within 26 weeks of the screening visit. If a serum creatinine drawn at the screening visit is > 20% higher than the serum creatinine drawn at the time of the 24 urine collection, the creatinine clearance must be re-evaluated by a repeat 24 hour urine test. If the new value is ≤80mg/dL the donor will be excluded. Meets institutional selection criteria for organ and bone marrow donation. Ability to understand and provide informed consent for all study procedures including kidney transplant and bone marrow harvest. Serologic evidence of prior EBV infection as documented by positive Immunoglobulin G (IgG) and negative Immunoglobulin M (IgM) antibodies against EBV. Exclusion Criteria: Recipient subjects who meet any of the following criteria will not be eligible for this study: Underlying renal disease with a high risk of disease recurrence in the transplanted kidney, including: Focal segmental glomerulosclerosis (FSGS). Type I or II membranoproliferative glomerulonephritis. Hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura. Clinically important genital/urinary tract dysfunction. Body mass index (BMI) > 40. Women who are breastfeeding. History of cancer within the last 5 years, except for nonmelanoma skin cancer, stage 1 renal cell carcinoma, stage 1 prostate cancers cured by local resection and any curatively treated carcinomas in situ. History of positive HIV-1 or HIV-2 serologies or nucleic acid test. Evidence of prior hepatitis B infection as evaluated by hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (anti-HBc IgM and IgG) and Hepatitis B surface antibody (anti-HBsAb). Subjects demonstrating any one of the following will be excluded: Positive hepatitis B surface antigen (HBsAg) or Positive anti-HBc IgM. Positive anti-HBc IgG. Positive Hepatitis B virus (HBV) Polymerase chain reaction (PCR). Positive anti-hepatitis C (HCV) antibodies and a positive serum HCV RNA PCR. All positive HCV antibody results must be assessed by an Electroimmunoassay (EIA) assay and confirmed by a quantitative serum HCV RNA assay. Participants with positive HCV antibodies but undetectable serum HCV RNA may be considered for eligibility. Participants with negative anti-HCV antibodies but unexplained liver enzyme abnormalities must undergo a quantitative serum RNA assay to rule out false negative HCV serologies. History of active Tuberculosis (TB). Any active, severe local or systemic infection at the screening visit. Autoimmune disease requiring immunosuppressive drugs for maintenance. Use of investigational drug, other than the study medications specified by the protocol, within 30 days of transplantation. Receipt of a live vaccine within 30 days of receipt of study therapy. The presence of any medical condition that the Investigator deems incompatible with participation in the trial. Donor subjects who meet any of the following criteria will not be eligible for this study: History of type I or type II diabetes mellitus. History of severe cardiovascular disease, defined as New York Heart Association Class III or IV. History of blood product donation to recipient. History of positive HIV-1 or HIV-2 serology or nucleic acid test. Evidence of prior hepatitis B infection. Subjects demonstrating any one of the following will be excluded: Positive hepatitis B surface antigen (HBsAg) or Positive anti- hepatitis B core antigen (HBc) IgM. Positive anti-HBc IgG. Positive HBV PCR Positive anti-hepatitis C (HCV) antibodies and a positive serum HCV RNA PCR. All positive HCV antibody results must be assessed by an EIA assay and confirmed by a quantitative serum HCV RNA assay. Participants with positive HCV antibodies but undetectable serum HCV RNA may be considered for eligibility. Participants with negative anti-HCV antibodies but unexplained liver enzyme abnormalities must undergo a quantitative serum RNA assay to rule out false negative HCV serologies. Autoimmune disease requiring immunosuppressive drugs for maintenance. The presence of any medical condition that the Investigator deems incompatible with participation in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RICG, BMT and high dose PT/Cy+SOC<br>Reduced-intensity conditioning regimen (RICG), bone marrow transplantation (BMT), high dose post-transplant cyclophosphamide (PT/Cy) and Standard of Care (SOC). Participants will receive: ATG (pre-transplant), pre-medicated with acetaminophen, diphenhydramine; steroid taper of methylprednisolone; fludarabine (2-6 days before transplant), and low-dose cyclophosphamide (pre- transplant); total body irradiation the day before transplant. Participants will receive a living renal transplant followed by BMT. High-dose cyclophosphamide will be given on days 3 and 4 post-transplant with MESNA. Filgrastim will be given on day 5 post-transplant and continue until absolute neutrophil recovery. Standard immunosuppression of tacrolimus, MMF, and prednisone will begin on day 5 post-transplant and be given ≥26 weeks post-transplant. Eligible participants will be gradually withdrawn from medication over a period of 24-40 weeks. | Biological: anti-thymocyte globulin<br>* An initial dose of 0.5 mg/kg IV will be administered over 6 hours on Day -9. Thereafter the daily dose will be increased to 2 mg/kg IV given over 4 hours on Days -8 and -7. No more than 150 mg of ATG may be administered per day.<br>* Other names: Thymoglobulin;Drug: Fludarabine<br>* Fludarabine at dose 30 mg/m^2 will be administered daily by intravenous infusion over 30 minutes on Day -6 to Day -2.<br>Drug: Cyclophosphamide<br>* Low dose pre-transplant cyclophosphamide will be administered intravenously (IV) over 1- 2 hours, (depending on volume) on Days -6 and -5. The dose of pre-transplant cyclophosphamide is 14.5 mg/kg/day. High dose cyclophosphamide [50mg/kg (Ideal Body Weight)] will be administered on Day 3 post-transplant (within 60 to 72 hours of marrow infusion) and on Day 4 post-transplant. Cyclophosphamide will be given IV over 1-2 hours depending on volume.<br>* Other names: cytoxan;Radiation: Total Body Irradiation<br>* Total body irradiation, consisting of 200 centigray (cGy) Anterior-Posterior/Posterior-Anterior (AP/PA) with 4 Megavolts (MV) or 6 MV photons at 8-12 cGy/min at the point of prescription will be administered in a single day on Day -1.<br>* Other names: TBI;Drug: acetaminophen<br>* 650 mg orally prior to antithymocyte globulin infusion.<br>* Other names: Tylenol;Drug: diphenhydramine<br>* 25mg diphenhydramine orally prior to antithymocyte globulin infusion.<br>* Other names: benadryl;Drug: methylprednisolone<br>* On Days -9 to -7 methylprednisolone 1mg/kg IV 1 hour prior ATG. This dose may be repeated once 3 hours after the first dose of steroids. On Day -6 and -5, methylprednisolone 0.75 mg/kg/ IV as a single dose; on Days -4 and -3, methylprednisolone 0.5 mg/kg/ IV as a single dose; on Day -2 methylprednisolone 0.25 mg/kg/ IV as a single dose.<br>Biological: bone marrow transplant<br>* Unprocessed, unmanipulated bone marrow will be harvested from the donor and infused into the recipient on Day 0.<br>* Other names: BMT;Drug: MESNA<br>* A series of MESNA doses will be administered for each dose of high dose, post-transplant cyclophosphamide. The total daily dose of MESNA is equal to 80% of the total daily dose of cyclophosphamide.<br>* Other names: Mesnex;Drug: mycophenolate mofetil<br>* MMF will be administered at a dose of 15 mg/kg orally three times per day based upon actual body weight, with the maximum of 3 grams a day from Day 5 to 35. The dose will then be reduced to the standard 1 g twice daily thereafter.<br>* Other names: CellCept;Drug: prednisone<br>* Prednisone will be administered at a dose of 10 mg orally daily from Day 5 for 12 weeks. Thereafter the dose will be reduced to 5 mg orally daily.<br>Drug: filgrastim<br>* All recipients will receive 5 microgram/kg per day of filgrastim as a single, subcutaneous injection from Day 5 post-transplant until the absolute neutrophil count is greater than 1000/µl on three consecutive measurements over at least 2 days.<br>* Other names: neupogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Who Achieved Operational Tolerance | Operational tolerance is defined as remaining off all immunosuppression 52 weeks after completion of immunosuppression withdrawal, with no evidence of biopsy-proven allograft rejection and, with acceptable renal function defined as a serum creatinine that has increased no more than 25% above baseline at the primary endpoint visit. Baseline creatinine is defined as the average of the lowest three creatinine values during 2 to 4 weeks post-transplant, excluding days on dialysis. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval. | Transplantation through 52 Weeks after Discontinuation of All Immunosuppression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration in Days of Engraftment Syndrome in Transplanted Participants | Engraftment syndrome is a complication that can occur following bone marrow transplant. The presence of engraftment syndrome is diagnosed by monitoring the common symptoms, which include: fever, rash, fluid in the lungs, and serum creatinine values above 4 mg/dL occurring within a week of absolute neutrophil recovery (e.g., first day after three consecutive daily absolute neutrophil count ≥ 500 per µL), without apparent other cause. Duration (in days) is measured as the time from the start of the engraftment syndrome event to the end of the engraftment syndrome event. | Transplant to End of Study (Up to 25 months After Enrollment) | 
| Number of Transplanted Participants Who Died | Number of participant deaths after receiving a transplant per protocol. | Transplant to End of Study (Up to 25 months After Enrollment) | 
| Number of Transplanted Participants With Acute Renal Allograft Rejection | Acute renal allograft rejection demonstrated either by biopsy or clinically (when a biopsy could not be performed). This measure includes participants with biopsy proven acute renal allograft rejection and those that have creatinine values 25% or greater relative to baseline for over 72 hours. Baseline serum creatinine is defined as the average of the lowest three serum creatinine values during 2 to 4 weeks post-transplant, excluding days on dialysis. | Transplant to End of Study (Up to 25 months After Enrollment) | 
| Histological Severity of Biopsies Demonstrating Acute Rejection as Defined by Banff 2007 Classification Renal Allograft Pathology | This outcome includes results from biopsies with proven acute renal allograft rejection according to the 2007 Banff Classification Renal Allograft Pathology. A Banff result of indeterminate is not classified as rejection. | Transplant to End of Study (Up to 25 months After Enrollment) | 
| Number of Transplanted Participants With Chronic T Cell-Mediated or Antibody-Mediated Rejection | Outcome includes participants who experienced chronic T cell-mediated rejection, antibody-mediated rejection and progressive interstitial fibrosis/tubular atrophy (IF/TA), transplant glomerulopathy or chronic obliterative arteriopathy, without an alternative, non-rejection related cause. Reference: Banff 2007 Classification Renal Allograft Pathology definition of terms. | Transplant to End of Study (Up to 25 months After Enrollment) | 
| Number of Days Post-Transplant to the First Episode of Acute Rejection Requiring Treatment | Number of days post-transplant to the first episode of acute rejection that required treatment. This includes acute rejection episodes requiring treatment that were not biopsy proven. | Transplant to End of Study (Up to 25 months After Enrollment) | 
| Number of Adverse Events (AEs)- Including Infection, Wound Complications, Post-transplant Diabetes, Hemorrhagic Cystitis and Malignancy | AEs reported as an infection, wound complication, post-transplant diabetes, hemorrhagic cystitis and/or malignancy. | First Dose of Study Medication to End of Study (Up to 25 Months After Enrollment) | 
| Number of Adverse Events (AEs) by Severity- Including Infection, Wound Complications, Post-Transplant Diabetes, Hemorrhagic Cystitis and Malignancy | AEs reported as an infection, wound complication, post-transplant diabetes, hemorrhagic cystitis and/or malignancy. Grades are based on National Cancer Institute--Common Terminology Criteria (NCI-CTCAE) Version 4.0. | First Dose of Study Medication to End of Study (Up to 25 Months After Enrollment) | 
| Duration in Days of Adverse Events (AEs)- Including Infection, Wound Complications, Post-transplant Diabetes, Hemorrhagic Cystitis and Malignancy | AEs reported as an infection, wound complication, post-transplant diabetes, hemorrhagic cystitis and/or malignancy. Time (in days) from the start date of the AE until the end date of the AE. Two events contributed to this calculation. | First Dose of Study Medication to End of Study (Up to 25 Months After Enrollment) | 
| Number of Transplanted Participants Who Developed Donor- Specific Antibody After Initiation of Immunosuppression Withdrawal | Donor-specific antibodies are directed against antigens expressed on donor organs. These antibodies can result in an immune attack on the transplanted organ, increasing risk of graft loss and/or rejection. | Initiation of Immunosuppression Withdrawal to End of Study (to 25 months) | 
| Number of Transplanted Participants Who Developed Donor-Specific Antibody During Study Participation | Donor-specific antibodies are directed against antigens expressed on donor organs. These antibodies can result in an immune attack on the transplanted organ, increasing risk of graft loss and/or rejection. | Transplant to End of Study (Up to 25 months) | 
| Number of Days From Neutrophil Nadir to Absolute Neutrophil Recovery | Time (in days) from neutrophil nadir, the first day post-transplant on which the absolute neutrophil count (ANC) is below 500 per µL, to the first day after three consecutive daily ANCs ≥ 500 per µL. ANC is a measure of the number of neutrophils present in the blood. Neutrophils are a type of white blood cell that fight against infection. A healthy person has an ANC between 2,500 and 6,000 per µL. A value below 500 per µL means the risk of infection is higher. | Post-Transplant Neutrophil Nadir to Neutrophil Recover | 
| Number of Days From Transplant to Platelet Count Recovery | Time (in days) from transplant to the first day of a platelet count of ≥20,000 per μL without a prior platelet transfusion in the preceding seven days. Low platelet numbers is associated with increased risk of bleeding and bruising. A healthy person has a platelet count ranging from 150,000 to 450,000 platelets per microliter of blood. | Transplant to Platelet Count Recovery | 
| Number of Transplanted Participants Who Remained Off Immunosuppression for at Least 52 Weeks, Including Those in Whom the 52 Week Biopsy Was Not Performed | Number of transplanted participants who remained off immunosuppression for ≥52 weeks, including those in whom the 52 week biopsy was not performed. This outcome included participants who were able to withdrawal successfully from all immunosuppression medication and remain off all immunosuppression for 52 weeks after the completion of withdrawal. | Transplant to 52 Weeks after Discontinuation of All Immunosuppression | 
| Number of Participants Free From Return to Immunosuppression for the Duration of the Study | Participants who were able to withdrawal successfully from all immunosuppression medication and remained off all immunosuppression medication for the remainder of the study. | Transplant to End of Study (Up to 25 Months) | 
| Number of Participants Experiencing an Incidence of Graft-versus-Host Disease Post-Transplant | Graft-versus-host disease (GVHD) is a medical complication that can occur after a person receives transplanted tissue, most commonly occurring after a bone marrow transplant. The white blood cells from the donated tissue recognize the tissue recipient's cells as foreign. These donor cells then attack the recipient's cells. | Transplant to Two Years Post-Transplant | 
| Severity of Graft-versus-Host Disease in Transplanted Participants | Graft-versus-host disease (GVHD) is a medical complication that can occur after a person receives transplanted tissue, most commonly occurring after a bone marrow transplant. The white blood cells from the donated tissue recognize the tissue recipient's cells as foreign. These donor cells then attack the recipient's cells. Severity of GVHD is based on skin, liver, and intestinal tract symptoms, ranging from I to IV, with IV being the worst. This measure counts the number of participants experiencing GVHD by severity. | Transplant to Two Years Post-Transplant | 
| Duration in Days of Graft-versus-Host Disease in Transplanted Participants | Graft-versus-host disease (GVHD) is a medical complication that can occur after a person receives transplanted tissue, most commonly occurring after a bone marrow transplant. The white blood cells from the donated tissue recognize the tissue recipient's cells as foreign. These donor cells then attack the recipient's cells. Duration (in days) is measured as the time from the start of the GVHD event to the end of the GVHD event. | Transplant to Two Years Post-Transplant | 
| Number of Transplanted Participants With Engraftment Syndrome | Engraftment syndrome is a complication that can occur following bone marrow transplant. The presence of engraftment syndrome is diagnosed by monitoring the common symptoms, which include: fever, rash, fluid in the lungs, and serum creatinine values above 4 mg/dL occurring within a week of absolute neutrophil recovery (e.g., first day after three consecutive daily absolute neutrophil counts ≥ 500 per µL), without apparent other cause. | Transplant to End of Study (Up to 25 months After Enrollment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal transplantation, conditioning regimen, BMT, high dose post-transplant cyclophosphamide (PT/Cy), renal allograft tolerance, immunosuppression withdrawal