Clinical trial NCT03591302: Delayed Blood Stem Transplantation in HLA Matched Kidney Transplant Recipients to Eliminate Immunosuppressive Drugs.
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 .
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Immune Tolerance
Keywords: Kidney Transplantation
Blood Stem Cell Transplantation
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2018-07-19
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+ and T Cell Transfusion in previous HLA Matched Living Donor Kidney Transplantation
Primary purpose: TREATMENT

Brief 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Globulin (rATG) and an HLA matched donor hematopoietic progenitor cell infusion such that their drugs are successfully withdrawn while maintaining normal renal function.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of patients no longer dependent on immunosuppressive drugs to maintain normal renal function.
timeFrame: six months to up to five years post stem cell transplant
Secondary outcomes:
measure: Percentage of patients experiencing biopsy proven rejection episodes requiring treatment requiring corticosteroids.
timeFrame: One year to five years
measure: Percentage of patients experiencing graft loss.
timeFrame: One year to five years
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
Study officials:
affiliation: Stanford University
name: Samuel Md Strober, MD
role: STUDY_CHAIR
References:
citation: 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.
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. No abstract available.
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.
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.
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.