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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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SLE Nephritis, CKD Stage 4, SIOD, Cystinosis, FSGS

Intervention / Treatment
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* Drug: Cyclophosphamide 1200 mg/Kg
* Drug: Fludarabine
* Drug: Cyclophosphamide 100 mg/Kg
* Radiation: Total Body Irradiation
* Drug: ATG
* Drug: Rituximab
* Drug: Melphalan
* Device: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System
* Procedure: Kidney Transplant


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 30 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study has two cohorts (Cohort 1b which will be safety lead-in with 4 patients, and then cohort 2a of 8 patients). The data generated will be compared with historical data available on outcomes of KT performed as SoC in this patient population.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1b: Conditioning Regimen A<br>An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT. | Drug: Cyclophosphamide 1200 mg/Kg<br>* Cyclophosphamide 1200 mg/Kg will be administered as part of the conditioning regimen A prior to HSCT<br>Drug: Fludarabine<br>* 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<br>Radiation: Total Body Irradiation<br>* Total Body Irradiation 200 cGy will be administered as part of the conditioning regimen prior to HSCT<br>* Other names: TBI;Drug: ATG<br>* ATG 7.5 mg/Kg will be administered as part of the conditioning regimen prior to HSCT<br>Drug: Rituximab<br>* Rituximab 200 mg/m2 will be administered within 24 hours of the HSCT<br>Device: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System<br>* 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.<br>Procedure: Kidney Transplant<br>* 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<br>|
| Experimental: Cohort 2a: Conditioning Regimen A<br>If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b. | Drug: Cyclophosphamide 1200 mg/Kg<br>* Cyclophosphamide 1200 mg/Kg will be administered as part of the conditioning regimen A prior to HSCT<br>Drug: Fludarabine<br>* 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<br>Radiation: Total Body Irradiation<br>* Total Body Irradiation 200 cGy will be administered as part of the conditioning regimen prior to HSCT<br>* Other names: TBI;Drug: ATG<br>* ATG 7.5 mg/Kg will be administered as part of the conditioning regimen prior to HSCT<br>Drug: Rituximab<br>* Rituximab 200 mg/m2 will be administered within 24 hours of the HSCT<br>Device: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System<br>* 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.<br>Procedure: Kidney Transplant<br>* 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<br>|
| Experimental: Cohort 1b: Conditioning Regimen B<br>An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT. | Drug: Fludarabine<br>* 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<br>Drug: Cyclophosphamide 100 mg/Kg<br>* Cyclophosphamide 100 mg/Kg will be administered as part of the conditioning regimen B prior to HSCT<br>Radiation: Total Body Irradiation<br>* Total Body Irradiation 200 cGy will be administered as part of the conditioning regimen prior to HSCT<br>* Other names: TBI;Drug: ATG<br>* ATG 7.5 mg/Kg will be administered as part of the conditioning regimen prior to HSCT<br>Drug: Rituximab<br>* Rituximab 200 mg/m2 will be administered within 24 hours of the HSCT<br>Drug: Melphalan<br>* Melphalan 100 mg/m2 will be administered as part of the conditioning regimen prior to HSCT<br>Device: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System<br>* 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.<br>Procedure: Kidney Transplant<br>* 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<br>|
| Experimental: Cohort 2a: Conditioning Regimen B<br>If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b. | Drug: Fludarabine<br>* 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<br>Drug: Cyclophosphamide 100 mg/Kg<br>* Cyclophosphamide 100 mg/Kg will be administered as part of the conditioning regimen B prior to HSCT<br>Radiation: Total Body Irradiation<br>* Total Body Irradiation 200 cGy will be administered as part of the conditioning regimen prior to HSCT<br>* Other names: TBI;Drug: ATG<br>* ATG 7.5 mg/Kg will be administered as part of the conditioning regimen prior to HSCT<br>Drug: Rituximab<br>* Rituximab 200 mg/m2 will be administered within 24 hours of the HSCT<br>Drug: Melphalan<br>* Melphalan 100 mg/m2 will be administered as part of the conditioning regimen prior to HSCT<br>Device: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System<br>* 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.<br>Procedure: Kidney Transplant<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients who are able to discontinue immunosuppression post-KT | Donor chimerism equal or greater to 95% after successful HSCT/KT therapy allows for withdrawal of immunosuppressive therapy in patient | Day +90 post-KT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with successful kidney function | Normal renal function as measured by the glomerular filtration rate (GFR) using the CKiD Under 25 (U25) formula that includes the serum creatinine and the Cystatin C, along with normal protein excretion. | +1 year post-KT | 
| Number of patients with myloid engraftment | Cumulative incidence of donor myeloid engraftment by Day +42 post-HSCT. Myeloid engraftment is defined as ANC of > 0.5 x 109/L for three consecutive laboratory values obtained on different days. Date of myeloid engraftment is the first date of the three lab values taken. | Day +42 post-HSCT | 
| Number of patients with persistent full donor chimerism | >95% donor chimerism for myeloid and lymphoid cells as assessed by peripheral blood (total, CD15+, CD3+, CD19+, CD56+, and CD34+) chimerism by Short Tandem Repeat (STR) or next-generation sequencing (NGS) analysis | Day +180 and 1 year post-KT | 
| Number of patients with acute GvHD | Cumulative incidence of acute GvHD (graded as II-IV and III-IV using the Magic criteria) | Day +90 and Day +180 post-HSCT | 
| Number of patients with chronic GvHD | Cumulative incidence of chronic GvHD by NIH consensus criteria | +1 year post-HSCT | 
| Number of patients with de novo acute GVHD | Cumulative incidence of de novo acute GvHD (graded as II-IV and III-IV using the Magic criteria) | +1 year post-KT | 
| Number of patients with de novo chronic GVHD | Cumulative incidence of de novo chronic GVHD as measured by NIH consensus criteria | +1 year post-KT | 
| Number of patients with functional tolerance to donor cells | Lack of recipient immune response to donor cells when tested with mixed lymphocyte culture | 6- and 12-months post-KT | 
| Number of cases of secondary malignancies | New incidence of secondary malignancies in patients after study participation | +5 year post-KT |