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

Alice Bertaina

Status and phase

Enrolling

Phase 2

Phase 1

Conditions

Cystinosis

FSGS

SIOD

SLE Nephritis

CKD Stage 4

Treatments

Drug: Fludarabine

Drug: Melphalan

Drug: ATG

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

Radiation: Total Body Irradiation

Procedure: Kidney Transplant

Drug: Cyclophosphamide 1200 mg/Kg

Drug: Rituximab

Drug: Cyclophosphamide 100 mg/Kg

Study type

Interventional

Funder types

Other

Identifiers

NCT05508009

IRB-65421

Details and patient eligibility

About

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.

Enrollment

12 estimated patients

Sex

All

Ages

1 to 30 years old

Volunteers

No Healthy Volunteers

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 design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Sequential Assignment

Masking

None (Open label)

12 participants in 4 patient groups

Cohort 1b: Conditioning Regimen A

Experimental group

Description:

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.

Treatment:

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

Drug: ATG

Radiation: Total Body Irradiation

Drug: Cyclophosphamide 1200 mg/Kg

Procedure: Kidney Transplant

Drug: Fludarabine

Drug: Rituximab

Cohort 2a: Conditioning Regimen A

Experimental group

Description:

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.

Treatment:

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

Drug: ATG

Radiation: Total Body Irradiation

Drug: Cyclophosphamide 1200 mg/Kg

Procedure: Kidney Transplant

Drug: Fludarabine

Drug: Rituximab

Cohort 1b: Conditioning Regimen B

Experimental group

Description:

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.

Treatment:

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

Drug: ATG

Drug: Cyclophosphamide 100 mg/Kg

Drug: Melphalan

Radiation: Total Body Irradiation

Procedure: Kidney Transplant

Drug: Fludarabine

Drug: Rituximab

Cohort 2a: Conditioning Regimen B

Experimental group

Description:

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.

Treatment:

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

Drug: ATG

Drug: Cyclophosphamide 100 mg/Kg

Drug: Melphalan

Radiation: Total Body Irradiation

Procedure: Kidney Transplant

Drug: Fludarabine

Drug: Rituximab