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NCT Number: NCT05508009

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

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.

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Key information

Conditions

SIOD Autoimmune Diseases CKD Stage 4 Congenital, Hereditary, and Neonatal Diseases and Abnormalities Connective Tissue Diseases Cystinosis FSGS Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genetic Diseases, Inborn Glomerulonephritis Immune System Diseases Kidney Diseases Lupus Erythematosus, Systemic Lupus Nephritis Lysosomal Storage Diseases Male Urogenital Diseases Metabolic Diseases Metabolism, Inborn Errors Nephritis Nutritional and Metabolic Diseases SLE Nephritis Skin and Connective Tissue Diseases Urogenital Diseases Urologic Diseases

Age range

1 year–30 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Lucile Packard Children's Hospital

Palo Alto, California, 94305, United States

Location status: Recruiting

Location contact

Alice Bertaina, MD

PRINCIPAL_INVESTIGATOR

David Shyr, MD

SUB_INVESTIGATOR

Orly Klein, MD

SUB_INVESTIGATOR

Paul Grimm, MD

PRINCIPAL_INVESTIGATOR

SCGT Clinical Trials Program

CONTACT

[email protected]

650-723-0912

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Anticipated need for kidney transplant due to:

a. Underlying genetic/immunologic disease the following conditions i. SIOD ii. FSGS iii. Cystinosis iv. SLE v. Membranoproliferative glomerulonephritis vi. Renal vasculitis characterized by positivity of the presence of ANCA vii. Other genetic diseases leading to kidney disease requiring KT Or b. Patients who have rejected a previous KT regardless of the underlying disease

  • 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.
  • Able to give informed consent or have an LAR available to provide consent
  • Male and female subjects of childbearing potential must agree to use an effective means of birth control to avoid pregnancy throughout the transplant procedure, while on immunosuppression, and if the subject experiences any cGvHD

Exclusion criteria

  • 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
  • Current active infectious disease. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
  • Serious concurrent uncontrolled medical disorders except for primary disease leading to chronic kidney disease
  • Lack of patient/parent/guardian informed consent
  • Any severe concurrent disease which, in the judgement of the investigator would place the patient at increased risk during participation in the study

Treatment and study plan

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

Other names: TBI

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

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

Primary outcomes

  1. Number of patients who are able to discontinue immunosuppression post-KT

    Time frame: Day +90 post-KT

    Donor chimerism equal or greater to 95% after successful HSCT/KT therapy allows for withdrawal of immunosuppressive therapy in patient

Secondary outcomes

  1. Number of patients with successful kidney function

    Time frame: +1 year post-KT

    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.

  2. Number of patients with myloid engraftment

    Time frame: Day +42 post-HSCT

    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.

  3. Number of patients with persistent full donor chimerism

    Time frame: Day +180 and 1 year post-KT

    >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

  4. Number of patients with acute GvHD

    Time frame: Day +90 and Day +180 post-HSCT

    Cumulative incidence of acute GvHD (graded as II-IV and III-IV using the Magic criteria)

  5. Number of patients with chronic GvHD

    Time frame: +1 year post-HSCT

    Cumulative incidence of chronic GvHD by NIH consensus criteria

  6. Number of patients with de novo acute GVHD

    Time frame: +1 year post-KT

    Cumulative incidence of de novo acute GvHD (graded as II-IV and III-IV using the Magic criteria)

  7. Number of patients with de novo chronic GVHD

    Time frame: +1 year post-KT

    Cumulative incidence of de novo chronic GVHD as measured by NIH consensus criteria

  8. Number of patients with functional tolerance to donor cells

    Time frame: 6- and 12-months post-KT

    Lack of recipient immune response to donor cells when tested with mixed lymphocyte culture

  9. Number of cases of secondary malignancies

    Time frame: +5 year post-KT

    New incidence of secondary malignancies in patients after study participation

Sponsors and collaborators

Lead sponsor

Alice Bertaina

Other

Collaborators

  • California Institute for Regenerative Medicine (CIRM)

Registry information

Official study title

Phase 1b/2a Trial of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) From an HLA-partially Matched Related or Unrelated Donor After TCRαβ+ T-cell/CD19+ B-cell Depletion for Patients Who Will Receive a Kidney Transplant (KT) From the Same HSCT/KT Donor

Important dates

Study start
2023
Primary completion
2032
Study completion
2034
First posted
Aug 19, 2022
Registry last updated
Jul 17, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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