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Early Trial of Allogeneic Hematopoietic Stem Cell Transplantation for Patients Who Will Receive a Kidney Transplant From the Same Donor

ConditionsSIODCystinosisFSGSSLE NephritisCKD Stage 4
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age1-30
SponsorAlice Bertaina

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Chronic kidney disease (CKD) stage 3 or greater

Steroids < 0.5 mg/Kg/day

The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB1

Lansky/Karnofsky score > 50; the Karnofsky Scale will be used in subjects ≥ 16 years of age, and the Lansky Scale will be used for those < 16 years of age.

Disqualifiers

Pregnant or lactating females.

Greater than Grade II aGvHD or severe, unmanaged extensive cGvHD due to a previous allograft at the time of inclusion

Dysfunction of liver (ALT/AST > 10 times upper normal value, or direct bilirubin > 3 times upper normal value), unmanageable dysfunction of renal function while undergoing dialysis

Severe cardiovascular disease at the time of evaluation unresponsive to nutritional and dialytic support (left ventricular ejection fraction < 40%), or clinical or echocardiographic evidence of severe diastolic dysfunction

Trial design

Design model

Sequential

Treatments tested in this trial

  • Cyclophosphamide 1200 mg/Kg

    Drug

    Cyclophosphamide 1200 mg/Kg will be administered as part of the conditioning regimen A prior to HSCT

  • Fludarabine

    Drug

    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

    Drug

    Cyclophosphamide 100 mg/Kg will be administered as part of the conditioning regimen B prior to HSCT

  • Total Body Irradiation

    Radiation

    Total Body Irradiation 200 cGy will be administered as part of the conditioning regimen prior to HSCT

  • ATG

    Drug

    ATG 7.5 mg/Kg will be administered as part of the conditioning regimen prior to HSCT

  • Rituximab

    Drug

    Rituximab 200 mg/m2 will be administered within 24 hours of the HSCT

  • Melphalan

    Drug

    Melphalan 100 mg/m2 will be administered as part of the conditioning regimen prior to HSCT

  • CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System

    Device

    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.

  • Kidney Transplant

    Procedure/Surgery

    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

Treatment groups

12 Participants
are divided into 4 treatment groups
Group A: Cohort 1b: Conditioning Regimen AExperimental treatment 7 interventions
Group B: Cohort 2a: Conditioning Regimen AExperimental treatment 7 interventions
Group C: Cohort 1b: Conditioning Regimen BExperimental treatment 8 interventions
Group D: Cohort 2a: Conditioning Regimen BExperimental treatment 8 interventions

Trial outcomes

Primary outcomes

1

Number 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

Secondary outcomes

1

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
2

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
3

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
4

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

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Alice Bertaina

Lead sponsor

Stanford University

Sponsor institution

California Institute for Regenerative Medicine (CIRM)

Collaborator

Source ClinicalTrials.gov
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