Delayed Blood Stem Transplantation in HLA Matched Kidney Transplant Recipients to Eliminate Immunosuppressive Drugs.

Immune Tolerance Clinical Trial

Official title:

Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+ and T-cell Transfusion to Withdraw Immunosuppressive Drugs From Recipients of a Previous HLA Matched Living Donor Kidney Transplantation .

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03591302
• Other study ID #: 46787
• Status: Recruiting
• Phase: Phase 1
• Start date: September 13, 2018
• Est. completion date: October 1, 2025

Study information

• Verified date: May 2022
• Source: Stanford University
• Contact: STEPHAN BUSQUE, MD
• Phone: 6504986189
• Email: sbusque[@]stanford.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study will determine whether patients with functioning Human Leukocyte Antigen (HLA) matched kidney transplants for at least one year and who want to discontinue immunosuppressive drugs can be treated with Total Lymphoid Irradiation (TLI) and rabbit Anti-Thymocyte Globulin (rATG) and an HLA matched donor hematopoietic progenitor cell infusion such that their drugs are successfully withdrawn while maintaining normal renal function.

Description:

This is a single-center, open-label study in adult renal transplant patients.Twenty five patients with functioning HLA matched living donor kidney transplants will receive TLI, rATG and an infusion of cluster of differentiation (CD)34+ (Stem/Progenitor cells) selected granulocyte colony-stimulating factor (G-CSF) mobilized blood cells combined with CD3+ T cells (Stem/ Progenitor cells) from their transplant donors.Transplant recipients will have their maintenance Immunosuppressive drugs adjusted for four weeks before starting the TLI and ATG conditioning regimen. Mycophenolate Mofetil (MMF) will be maintained at 0.5 gm twice a day per day during this four week period during TLI and ATG treatments, and increased to 1 gram twice a day immediately after the completion of TLI at day 14.

MMF will be tapered starting 6 (six) months later. Tacrolimus levels will be targeted to blood trough levels of 4-6 ng/ml in the month before the start of the conditioning regimen. This target would be increased to 8-10 ng/ml at the start of the TLI and ATG conditioning regimen. At serial time points (1) graft function will be monitored. (2) chimerism will be measured in recipient white blood cell subsets, (3) protocol biopsies of the graft will be obtained. An attempt will be made to discontinue Tacrolimus at 12 months if (1) chimerism is detectable for least 180 days after the CD34+ and CD3+ cell infusion, (2) there is no Graft Versus Host Disease (GVHD), (3) there is stable graft function without clinical rejection episodes and (4) lack of histological rejection on protocol biopsies.

Recipients will be given the target dose of ≥ 8 x 10^6 CD 34 + cells/Kg and a dose of 5x10^6 CD3+ cells/Kg.The dose would be sequentially increased to 10, 15 and 25 x 10^6 CD3+ cells/Kg if fewer than 4 of 5 consecutive patients achieve whole blood chimerism of ≥ 30 % at 60 days. If 4 of 5 patients achieve this level of chimerism, then all subsequent enrolled patients will receive this dose.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: October 1, 2025
• Est. primary completion date: October 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. All consenting adults of age 18 years and older with previous HLA matched sibling living donor renal transplants who still have their HLA- matched kidney donor available, and who have no history of acute or chronic rejection.

2. Patients who agree to participate in the study and sign an Informed Consent

3. The HLA-matched donor meets the Stanford Bone Marrow Transplant criteria for stem cell donation, agrees to participate and has signed an Informed Consent.

4. The pair is confirmed to be HLA-matched (2 haplo type match) as determined by the histocompatibility laboratory at Stanford.

5. Patients who have no known contraindication to the administration of rabbit ATG or radiation

6. Males and females of reproductive potential who agree to practice a reliable form of contraception for at least 18 months post transplant.

Exclusion Criteria:

1. Known allergy to ATG or a known allergy to rabbit proteins.

2. History of malignancy with the exception of non-melanoma skin malignancies.

3. Pregnant women or nursing mothers.

4. Serological evidence of HIV, Hepatitis B (HepBsAg+) or Hepatitis C infection.

5. Leukopenia (with a white blood cell count < 3000/mm3) or thrombocytopenia (platelet count < 100,000/mm3)

6. Previous history of acute or chronic rejection of the kidney transplant or recurrence of the original disease.

7. Screening kidney biopsy demonstrating acute or chronic rejection, recurrence of original disease or interstitial fibrosis/Tubular Atrophy (IF/TA) score greater than 1.

Related Conditions & MeSH terms

• Immune Tolerance

Intervention

Biological:
• Hematopoietic cell transplantation
Transplantation of hematopoietic stem cells from living donor.

Radiation:
• Total Lymphoid irradiation
Total lymphoid irradiation is used as part of the conditioning regimen for the hematopoietic stem cell transplant.

Locations

Country	Name	City	State
United States	Stanford University Medical Center	Palo Alto	California

Sponsors (1)

Lead Sponsor	Collaborator
Stephan Busque

Country where clinical trial is conducted

United States, 

References & Publications (5)

Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA, Hoppe RT, Lowsky R, Engleman EG, Strober S. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med. 2008 Jan 24;358(4):362-8. doi: 10.1056/NEJMoa074191. — View Citation

Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Sarwal M, Millan MT, Shizuru JA, Lowsky R, Engleman EG, Strober S. Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants. Am J Transplant. 2012 May;12(5):1133-45. doi: 10.1111/j.1600-6143.2012.03992.x. Epub 2012 Mar 8. — View Citation

Scandling JD, Busque S, Lowsky R, Shizuru J, Shori A, Engleman E, Jensen K, Strober S. Macrochimerism and clinical transplant tolerance. Hum Immunol. 2018 May;79(5):266-271. doi: 10.1016/j.humimm.2018.01.002. Epub 2018 Jan 9. Review. — View Citation

Scandling JD, Busque S, Shizuru JA, Engleman EG, Strober S. Induced immune tolerance for kidney transplantation. N Engl J Med. 2011 Oct 6;365(14):1359-60. doi: 10.1056/NEJMc1107841. — View Citation

Scandling JD, Busque S, Shizuru JA, Lowsky R, Hoppe R, Dejbakhsh-Jones S, Jensen K, Shori A, Strober JA, Lavori P, Turnbull BB, Engleman EG, Strober S. Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. Am J Transplant. 2015 Mar;15(3):695-704. doi: 10.1111/ajt.13091. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of patients no longer dependent on immunosuppressive drugs to maintain normal renal function.	A patient will be considered no longer dependent if able to maintain normal renal function after coming off immunosuppressive medications.	six months to up to five years post stem cell transplant
Secondary	Percentage of patients experiencing biopsy proven rejection episodes requiring treatment requiring corticosteroids.		One year to five years
Secondary	Percentage of patients experiencing graft loss.		One year to five years