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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	1 Year - 30 Years
Gender	All

More Inclusion & Exclusion Criteria

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

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT05508009
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 1/Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Alice Bertaina
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Alice Bertaina, MDPaul Grimm, MD
Principal Investigator Affiliation	Stanford UniversityStanford University
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	SIOD, Cystinosis, FSGS, SLE Nephritis, CKD Stage 4

Arms & Interventions

Arms

Experimental: Cohort 1b: Conditioning Regimen A

An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.

Experimental: Cohort 2a: Conditioning Regimen A

If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.

Experimental: Cohort 1b: Conditioning Regimen B

An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.

Experimental: Cohort 2a: Conditioning Regimen B

If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.

Interventions

Drug: - Cyclophosphamide 1200 mg/Kg

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

Drug: - Fludarabine

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

Drug: - Cyclophosphamide 100 mg/Kg

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

Radiation: - Total Body Irradiation

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

Drug: - ATG

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

Drug: - Rituximab

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

Drug: - Melphalan

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

Device: - CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System

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.

Procedure: - Kidney Transplant

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

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Lucile Packard Children's Hospital, Palo Alto 5380748, California 5332921

Status

Recruiting

Address

Lucile Packard Children's Hospital

Palo Alto 5380748, California 5332921, 94305

Site Contact

SCGT Clinical Trials Program

[email protected]

650-723-0912

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