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

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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Immune Tolerance
• Intervention / Treatment: Biological: Combined Deceased Donor Kidney and Hematopoietic Cell Transplants

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Subjects will be withdrawn from the immunosuppression if they have met the withdrawal criteria.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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%.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I Study of Combined DD Kidney and HCT Transplant; 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; 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.; Other Names: Radiation

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Robert Lowsky, MD, Stanford University; Principal Investigator: Stephan Busque, MD, Stanford University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2022
• Primary Completion (Anticipated): October 1, 2025
• Study Completion (Anticipated): October 1, 2029

Study Registration Dates

• First Submitted: September 17, 2020
• First Submitted That Met QC Criteria: September 25, 2020
• First Posted (Actual): September 30, 2020

Study Record Updates

• Last Update Posted (Actual): May 11, 2022
• Last Update Submitted That Met QC Criteria: May 6, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: 57511

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No