RECRUITINGPhase 1 / Phase 2INTERVENTIONAL

Early Trial of Allogeneic Hematopoietic Stem Cell Transplantation for Patients Who Will Receive a Kidney Transplant From the Same Donor

Phase 1b/2a Trial of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) From an HLA-partially Matched Related or Unrelated Donor After TCRαβ+ T-cell/CD19+ B-cell Depletion for Patients Who Will Receive a Kidney Transplant (KT) From the Same HSCT/KT Donor

About This Trial

This is a single center, non-randomized, non-controlled open-label phase 1b/2a trial of performing sequential αβdepleted-HSCT and KT in patients requiring KT to prevent kidney rejection post-KT, in the absence of any post-KT immunosuppression, to abrogate the need for lifelong immunosuppression, the risk of chronic rejection and, ultimately, the need for repeated transplantation.

Who May Be Eligible (Plain English)

Who May Qualify: - Anticipated need for kidney transplant due to: a. Underlying genetic/immunologic disease the following conditions i. SIOD ii. FSGS iii. Cystinosis iv. SLE v. Membranoproliferative glomerulonephritis vi. Renal vasculitis characterized by positivity of the presence of ANCA vii. Other genetic diseases leading to kidney disease requiring KT Or b. Patients who have rejected a previous KT regardless of the underlying disease - Chronic kidney disease (CKD) stage 3 or greater - Steroids \< 0.5 mg/Kg/day - The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB1 - Lansky/Karnofsky score \> 50; the Karnofsky Scale will be used in subjects ≥ 16 years of age, and the Lansky Scale will be used for those \< 16 years of age. - Able to give willing to sign a consent form or have an LAR available to provide consent - Male and female subjects of childbearing potential must agree to use an effective means of birth control to avoid pregnancy throughout the transplant procedure, while on immunosuppression, and if the subject experiences any cGvHD Who Should NOT Join This Trial: - Pregnant or lactating females. - Greater than Grade II aGvHD or severe, unmanaged extensive cGvHD due to a previous allograft at the time of inclusion - Dysfunction of liver (ALT/AST \> 10 times upper normal value, or direct bilirubin \> 3 times upper normal value), unmanageable dysfunction of renal function while undergoing dialysis - Severe cardiovascular disease at the time of evaluation unresponsive to nutritional and dialytic support (left ventricular ejection fraction \< 40%), or clinical or echocardiographic evidence of severe diastolic dysfunction ...See full criteria on ClinicalTrials.gov Always talk to your doctor about whether this trial is right for you.

Original Eligibility Criteria

View original clinical language

Inclusion Criteria: * Anticipated need for kidney transplant due to: a. Underlying genetic/immunologic disease the following conditions i. SIOD ii. FSGS iii. Cystinosis iv. SLE v. Membranoproliferative glomerulonephritis vi. Renal vasculitis characterized by positivity of the presence of ANCA vii. Other genetic diseases leading to kidney disease requiring KT Or b. Patients who have rejected a previous KT regardless of the underlying disease * Chronic kidney disease (CKD) stage 3 or greater * Steroids \< 0.5 mg/Kg/day * The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB1 * Lansky/Karnofsky score \> 50; the Karnofsky Scale will be used in subjects ≥ 16 years of age, and the Lansky Scale will be used for those \< 16 years of age. * Able to give informed consent or have an LAR available to provide consent * Male and female subjects of childbearing potential must agree to use an effective means of birth control to avoid pregnancy throughout the transplant procedure, while on immunosuppression, and if the subject experiences any cGvHD Exclusion Criteria: * Pregnant or lactating females. * Greater than Grade II aGvHD or severe, unmanaged extensive cGvHD due to a previous allograft at the time of inclusion * Dysfunction of liver (ALT/AST \> 10 times upper normal value, or direct bilirubin \> 3 times upper normal value), unmanageable dysfunction of renal function while undergoing dialysis * Severe cardiovascular disease at the time of evaluation unresponsive to nutritional and dialytic support (left ventricular ejection fraction \< 40%), or clinical or echocardiographic evidence of severe diastolic dysfunction * Current active infectious disease. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load. * Serious concurrent uncontrolled medical disorders except for primary disease leading to chronic kidney disease * Lack of patient/parent/guardian informed consent * Any severe concurrent disease which, in the judgement of the investigator would place the patient at increased risk during participation in the study

Treatments Being Tested

DRUG

Cyclophosphamide 1200 mg/Kg

Cyclophosphamide 1200 mg/Kg will be administered as part of the conditioning regimen A prior to HSCT

DRUG

Fludarabine

Fludarabine (starting dose 0.5 mg/Kg and then PK guided to reach an AUC of 18-20) will be administered as part of the conditioning regimen prior to HSCT

DRUG

Cyclophosphamide 100 mg/Kg

Cyclophosphamide 100 mg/Kg will be administered as part of the conditioning regimen B prior to HSCT

RADIATION

Total Body Irradiation

Total Body Irradiation 200 cGy will be administered as part of the conditioning regimen prior to HSCT

DRUG

ATG

ATG 7.5 mg/Kg will be administered as part of the conditioning regimen prior to HSCT

DRUG

Rituximab

Rituximab 200 mg/m2 will be administered within 24 hours of the HSCT

DRUG

Melphalan

Melphalan 100 mg/m2 will be administered as part of the conditioning regimen prior to HSCT

DEVICE

CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System

CliniMACS® TCRαβ-Biotin and CD19 Systems will be used to create the mobilized peripheral blood stem cells (PBSC) from allogeneic donors depleted of TCRαβ+ T cells and CD19+ B cells to be infused into the patient for the HSCT. The target dose for the number of CD34+ HSC infused is \> 10 x 10\^6 cells/Kg recipient weight. The minimum dose is 2 x 10\^6 cells/Kg. There is no upper limit to the dose of CD34+ HSC infused as long as no more than 1 x 10\^5 TCRαβ+ T-cells/Kg are infused. The target dose of TCRαβ+ T cells/Kg is \< 0.50 x 10\^5.

PROCEDURE

Kidney Transplant

In the presence of donor myeloid engraftment, at least 3 months post-HSCT, with \> 95% donor CD3+ chimerism, in the absence of signs of active aGvHD or cGvHD (moderate or severe), at least 4 weeks off of immunosuppression for any previously occurring acute or chronic GvHD (except single agent treatment of mild cGvHD), and with a BMI \>18.5, ambulatory and active in addition to the eligibility for the standard of care KT criteria, patients will undergo a living donor KT using same donor as HSCT

Locations (1)

Lucile Packard Children's Hospital

Palo Alto, California, United States