Clinical trial NCT04571203: Kidney and Hematopoietic Cell Transplants Using a Regimen to Promote Hematopoietic Cell Engraftment
Official title: Phase I Study of Combined Deceased Donor Kidney and Hematopoietic Cell Transplants Using a Regimen to Promote Hematopoietic Cell Engraftment
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE1
Conditions: Immune Tolerance
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2020-09-30
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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Subjects will be withdrawn from the immunosuppression if they have met the withdrawal criteria.

Eligibility criteria: Inclusion Criteria:

RECIPIENT INCLUSION CRITERIA:

1. Patient is ≥ 18 years old, and \<65 years of age.
2. Has End Stage Renal Disease (ESRD) and is a de novo kidney transplant candidate part Stanford standard of care.
3. Listed with the Organ Procurement and Transplantation Network (OPTN) for deceased donor transplantation.
4. A serotypic (Human Leucocyte Antigen) HLA match with the donor of a least 1 locus in A, B or DR.
5. Males and females of reproductive potential who agree to practice a reliable form of contraception for at least 1 year post transplant.
6. Females have a negative serum pregnancy test.
7. Ability to understand and the willingness to sign a written informed consent document. Patients must have signed informed consent to participate in the trial.
8. No known contraindication to administration of rabbit ATG or low dose irradiation.

DONOR INCLUSION CRITERIA:

1. Brain dead donor aged ≥ 16 and ≤ 55
2. Organ Procurement Organization (OPO) consent for vertebral body procurement
3. Organ Procurement Organization consent for research
4. Projected cold ischemia time \<24 hours.

Exclusion Criteria:

RECIPIENT EXCLUSION CRITERIA:

1. Known allergy to rabbit protein.
2. History of malignancy with the exception of non melanoma skin malignancy.
3. Pregnant woman or nursing mother.
4. Body weight \>90kg or BMI \>35.
5. 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.
6. EBV (Epstein Bar Virus)Ab positive donor to EBV Ab negative recipient.
7. Active bacterial, viral or fungal infection defined as currently taking medication for the infection.
8. Leukopenia (white blood cell count \< 3000/mm3) or thrombocytopenia (with a platelet count \< 100,000/mm3).
9. 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.
10. Concern for alcohol or other substance abuse.
11. Kidney disease at high risk for post transplant recurrence: aHUS (atypical hemolytic- uremic syndrome) and C3 glomerulopathy
12. Panel reactive antibody (PRA) \>80%.
13. Positive donor specific antibody (DSA).
14. Prior or combined organ transplant.
15. Patients with \>5 pack year smoking history, smoking within 10 years of enrollment, or first degree relative with lung cancer.

DONOR EXCLUSION CRITERIA:

1. History of malignancy with the exception of non melanoma skin malignancy.
2. History of autoimmune disease.
3. Known medical diagnosis of Zika virus infection within the prior 6 months, including post mortem screening.
4. Serological evidence of HIV, Hepatitis B (surface antigen positive), or Hepatitis C infection.
5. Evidence of systemic infection.
6. Kidney Donor Profile Index (KDPI) \> 70%.

Primary outcomes:
measure: Number of patients out of the total patients enrolled who received both the kidney and the bone marrow from the same donor.
timeFrame: 6 months
measure: Determine the dose of TBI that will support donor CD3 Tcell chimerism between 30-75% at 45 days post infusion
timeFrame: day 45
Secondary outcomes:
measure: Number of patients who develop GVHD, all grades and types, within 60 months of kidney transplant
timeFrame: 60 months
measure: Number of patients with either bacterial, viral or fungal infection within 12 months post transplant .
timeFrame: 12 months
measure: Serum Creatinine
timeFrame: up to 60 months
measure: Panel-Reactive Antibody (PRA)
timeFrame: Baseline, month 9, and month 12
measure: Donor-Specific Antibody (DSA)
timeFrame: Baseline, month 9, and month 12
measure: Percentage of subjects on immunosuppressive medications after an eighteen month post transplant till month 60.
timeFrame: 60 months
measure: Persistence of donor chimerism >1%
timeFrame: 3,6,9,12,15,18,24,48,60 months
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Robert Lowsky, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Stephan Busque, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Busque S, Scandling JD, Lowsky R, Shizuru J, Jensen K, Waters J, Wu HH, Sheehan K, Shori A, Choi O, Pham T, Fernandez Vina MA, Hoppe R, Tamaresis J, Lavori P, Engleman EG, Meyer E, Strober S. Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal. Sci Transl Med. 2020 Jan 29;12(528):eaax8863. doi: 10.1126/scitranslmed.aax8863.