This is a single center, non-randomized, non-controlled open-label phase 1b/2a trial of performing sequential αβdepleted-HSCT and KT in patients requiring KT to prevent kidney rejection post-KT, in the absence of any post-KT immunosuppression, to abrogate the need for lifelong immunosuppression, the risk of chronic rejection and, ultimately, the need for repeated transplantation.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Cyclophosphamide 1200 mg/Kg will be administered as part of the conditioning regimen A prior to HSCT
Fludarabine (starting dose 0.5 mg/Kg and then PK guided to reach an AUC of 18-20) will be administered as part of the conditioning regimen prior to HSCT
Cyclophosphamide 100 mg/Kg will be administered as part of the conditioning regimen B prior to HSCT
Total Body Irradiation 200 cGy will be administered as part of the conditioning regimen prior to HSCT
ATG 7.5 mg/Kg will be administered as part of the conditioning regimen prior to HSCT
Rituximab 200 mg/m2 will be administered within 24 hours of the HSCT
Melphalan 100 mg/m2 will be administered as part of the conditioning regimen prior to HSCT
CliniMACS® TCRαβ-Biotin and CD19 Systems will be used to create the mobilized peripheral blood stem cells (PBSC) from allogeneic donors depleted of TCRαβ+ T cells and CD19+ B cells to be infused into the patient for the HSCT. The target dose for the number of CD34+ HSC infused is \> 10 x 10\^6 cells/Kg recipient weight. The minimum dose is 2 x 10\^6 cells/Kg. There is no upper limit to the dose of CD34+ HSC infused as long as no more than 1 x 10\^5 TCRαβ+ T-cells/Kg are infused. The target dose of TCRαβ+ T cells/Kg is \< 0.50 x 10\^5.
In the presence of donor myeloid engraftment, at least 3 months post-HSCT, with \> 95% donor CD3+ chimerism, in the absence of signs of active aGvHD or cGvHD (moderate or severe), at least 4 weeks off of immunosuppression for any previously occurring acute or chronic GvHD (except single agent treatment of mild cGvHD), and with a BMI \>18.5, ambulatory and active in addition to the eligibility for the standard of care KT criteria, patients will undergo a living donor KT using same donor as HSCT
Lucile Packard Children's Hospital
Palo Alto, California, United States
RECRUITINGNumber of patients who are able to discontinue immunosuppression post-KT
Donor chimerism equal or greater to 95% after successful HSCT/KT therapy allows for withdrawal of immunosuppressive therapy in patient
Time frame: Day +90 post-KT
Number of patients with successful kidney function
Normal renal function as measured by the glomerular filtration rate (GFR) using the CKiD Under 25 (U25) formula that includes the serum creatinine and the Cystatin C, along with normal protein excretion.
Time frame: +1 year post-KT
Number of patients with myloid engraftment
Cumulative incidence of donor myeloid engraftment by Day +42 post-HSCT. Myeloid engraftment is defined as ANC of \> 0.5 x 109/L for three consecutive laboratory values obtained on different days. Date of myeloid engraftment is the first date of the three lab values taken.
Time frame: Day +42 post-HSCT
Number of patients with persistent full donor chimerism
\>95% donor chimerism for myeloid and lymphoid cells as assessed by peripheral blood (total, CD15+, CD3+, CD19+, CD56+, and CD34+) chimerism by Short Tandem Repeat (STR) or next-generation sequencing (NGS) analysis
Time frame: Day +180 and 1 year post-KT
Number of patients with acute GvHD
Cumulative incidence of acute GvHD (graded as II-IV and III-IV using the Magic criteria)
Time frame: Day +90 and Day +180 post-HSCT
Number of patients with chronic GvHD
Cumulative incidence of chronic GvHD by NIH consensus criteria
Time frame: +1 year post-HSCT
Number of patients with de novo acute GVHD
Cumulative incidence of de novo acute GvHD (graded as II-IV and III-IV using the Magic criteria)
Time frame: +1 year post-KT
Number of patients with de novo chronic GVHD
Cumulative incidence of de novo chronic GVHD as measured by NIH consensus criteria
Time frame: +1 year post-KT
Number of patients with functional tolerance to donor cells
Lack of recipient immune response to donor cells when tested with mixed lymphocyte culture
Time frame: 6- and 12-months post-KT
Number of cases of secondary malignancies
New incidence of secondary malignancies in patients after study participation
Time frame: +5 year post-KT
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