Kidney and Hematopoietic Cell Transplants Using a Regimen to Promote Hematopoietic Cell Engraftment

Study Overview
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Brief Summary
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This is a single arm phase 1 non randomized dose finding study for safety, feasibility and efficacy of deceased donor vertebral body (VB) marrow cell infusion and kidney transplantation.

Detailed Description
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Patients will undergo a standard of care deceased donor kidney transplant and thereafter the recipient will receive TLI (Total Lymphoid Irradiation)/single low dose Total Body Irradiation, ATG (Anti-Thymocyte Globulin) conditioning, followed by an infusion of whole bone marrow cells harvested from the same donor vertebral bodies. Patients will be receive standard of care doses of steroids, MMF and tacrolimus as part of their transplant immunosuppression. Subjects will be withdrawn from the immunosuppression if they have met the withdrawal criteria.

Official Title
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Phase I Study of Combined Deceased Donor Kidney and Hematopoietic Cell Transplants Using a Regimen to Promote Hematopoietic Cell Engraftment

Conditions
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Immune Tolerance

Intervention / Treatment
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* Biological: Combined Deceased Donor Kidney and Hematopoietic Cell Transplants


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RECIPIENT INCLUSION CRITERIA: Patient is ≥ 18 years old, and <65 years of age. Has End Stage Renal Disease (ESRD) and is a de novo kidney transplant candidate part Stanford standard of care. Listed with the Organ Procurement and Transplantation Network (OPTN) for deceased donor transplantation. A serotypic (Human Leucocyte Antigen) HLA match with the donor of a least 1 locus in A, B or DR. Males and females of reproductive potential who agree to practice a reliable form of contraception for at least 1 year post transplant. Females have a negative serum pregnancy test. Ability to understand and the willingness to sign a written informed consent document. Patients must have signed informed consent to participate in the trial. No known contraindication to administration of rabbit ATG or low dose irradiation. DONOR INCLUSION CRITERIA: Brain dead donor aged ≥ 16 and ≤ 55 Organ Procurement Organization (OPO) consent for vertebral body procurement Organ Procurement Organization consent for research Projected cold ischemia time <24 hours. Exclusion Criteria: RECIPIENT EXCLUSION CRITERIA: Known allergy to rabbit protein. History of malignancy with the exception of non melanoma skin malignancy. Pregnant woman or nursing mother. Body weight >90kg or BMI >35. Evidence of HIV 1/2 antibody (Ab), HTLV 1 and HTLV 2 Ab (Human T-Lymphotropic Virus), Hepatitis B sAg (surface antigen), Hepatitis C Ab, or positive syphilis screen. EBV (Epstein Bar Virus)Ab positive donor to EBV Ab negative recipient. Active bacterial, viral or fungal infection defined as currently taking medication for the infection. Leukopenia (white blood cell count < 3000/mm3) or thrombocytopenia (with a platelet count < 100,000/mm3). Psychiatric disorder(s) or psychosocial circumstance(s) which in the opinion of the Stanford Transplant team caring for this potential patient would place the patient at an unacceptable risk. Concern for alcohol or other substance abuse. Kidney disease at high risk for post transplant recurrence: aHUS (atypical hemolytic- uremic syndrome) and C3 glomerulopathy Panel reactive antibody (PRA) >80%. Positive donor specific antibody (DSA). Prior or combined organ transplant. Patients with >5 pack year smoking history, smoking within 10 years of enrollment, or first degree relative with lung cancer. DONOR EXCLUSION CRITERIA: History of malignancy with the exception of non melanoma skin malignancy. History of autoimmune disease. Known medical diagnosis of Zika virus infection within the prior 6 months, including post mortem screening. Serological evidence of HIV, Hepatitis B (surface antigen positive), or Hepatitis C infection. Evidence of systemic infection. Kidney Donor Profile Index (KDPI) > 70%.

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
Interventional Model Description: End Stage Renal Disease subjects will receive a deceased donor kidney and vertebral body stem cell infusion. These transplant recipients post kidney transplant will undergo conditioning by ATG, Total Lymphoid irradiation and 1 single dose of TBI. Subsequently, the vertebral body stem cell infusion will be administered.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Study of Combined DD Kidney and HCT Transplant<br>Single arm Phase 1 non randomized dose finding study for safety, feasibility and efficacy of deceased donor vertebral body (VB) marrow cell infusion | Biological: Combined Deceased Donor Kidney and Hematopoietic Cell Transplants<br>* This combined kidney and hematopoietic cell transplants with a conditioning regimen with irradiation and ATG creates an environment of immune-tolerance. This promotes hematopoietic cell engraftment.<br>* Other names: Radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients out of the total patients enrolled who received both the kidney and the bone marrow from the same donor. |  | 6 months | 
| Determine the dose of TBI that will support donor CD3 Tcell chimerism between 30-75% at 45 days post infusion | TBI dose in cGy associated with donor Tcell chimerism of >30 % immunosuppressive drug monotherapy. | day 45 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients who develop GVHD, all grades and types, within 60 months of kidney transplant |  | 60 months | 
| Number of patients with either bacterial, viral or fungal infection within 12 months post transplant . |  | 12 months | 
| Serum Creatinine |  | up to 60 months | 
| Panel-Reactive Antibody (PRA) | Report % of PRA on all participants | Baseline, month 9, and month 12 | 
| Donor-Specific Antibody (DSA) | Report percentage of patients that develop DSA | Baseline, month 9, and month 12 | 
| Percentage of subjects on immunosuppressive medications after an eighteen month post transplant till month 60. |  | 60 months | 
| Persistence of donor chimerism >1% | Percentage of patients with donor chimerism (any lineage) | 3,6,9,12,15,18,24,48,60 months |