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

NCT05508009 | Recruiting Phase 1 DMC FDA Device

• 1 other identifier: IRB-65421
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

SIOD; Cystinosis; FSGS; SLE Nephritis; CKD Stage 4

Outcome Measures

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

  Day +90 post-KT

Secondary Outcomes (9)

• Number of patients with successful kidney function

  +1 year post-KT

• Number of patients with myloid engraftment

  Day +42 post-HSCT

• Number of patients with persistent full donor chimerism

  Day +180 and 1 year post-KT

• Number of patients with acute GvHD

  Day +90 and Day +180 post-HSCT

• Number of patients with chronic GvHD

  +1 year post-HSCT

Study Arms (4)

Cohort 1b: Conditioning Regimen A

EXPERIMENTAL

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.

Drug: Cyclophosphamide 1200 mg/Kg; Drug: Fludarabine; Radiation: Total Body Irradiation; Drug: ATG; Drug: Rituximab; Device: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System; Procedure: Kidney Transplant

Cohort 2a: Conditioning Regimen A

EXPERIMENTAL

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.

Drug: Cyclophosphamide 1200 mg/Kg; Drug: Fludarabine; Radiation: Total Body Irradiation; Drug: ATG; Drug: Rituximab; Device: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System; Procedure: Kidney Transplant

Cohort 1b: Conditioning Regimen B

EXPERIMENTAL

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.

Drug: Fludarabine; Drug: Cyclophosphamide 100 mg/Kg; Radiation: Total Body Irradiation; Drug: ATG; Drug: Rituximab; Drug: Melphalan; Device: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System; Procedure: Kidney Transplant

Cohort 2a: Conditioning Regimen B

EXPERIMENTAL

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.

Drug: Fludarabine; Drug: Cyclophosphamide 100 mg/Kg; Radiation: Total Body Irradiation; Drug: ATG; Drug: Rituximab; Drug: Melphalan; Device: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System; Procedure: Kidney Transplant

Interventions

Cyclophosphamide 1200 mg/Kg DRUG

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

Cohort 1b: Conditioning Regimen A; Cohort 2a: Conditioning Regimen A

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

Cohort 1b: Conditioning Regimen A; Cohort 1b: Conditioning Regimen B; Cohort 2a: Conditioning Regimen A; Cohort 2a: Conditioning Regimen B

Cyclophosphamide 100 mg/Kg DRUG

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

Cohort 1b: Conditioning Regimen B; Cohort 2a: Conditioning Regimen B

Total Body Irradiation RADIATION

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

Also known as: TBI

Cohort 1b: Conditioning Regimen A; Cohort 1b: Conditioning Regimen B; Cohort 2a: Conditioning Regimen A; Cohort 2a: Conditioning Regimen B

ATG DRUG

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

Cohort 1b: Conditioning Regimen A; Cohort 1b: Conditioning Regimen B; Cohort 2a: Conditioning Regimen A; Cohort 2a: Conditioning Regimen B

Rituximab DRUG

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

Cohort 1b: Conditioning Regimen A; Cohort 1b: Conditioning Regimen B; Cohort 2a: Conditioning Regimen A; Cohort 2a: Conditioning Regimen B

Melphalan DRUG

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

Cohort 1b: Conditioning Regimen B; Cohort 2a: Conditioning Regimen B

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.

Cohort 1b: Conditioning Regimen A; Cohort 1b: Conditioning Regimen B; Cohort 2a: Conditioning Regimen A; Cohort 2a: Conditioning Regimen B

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

Cohort 1b: Conditioning Regimen A; Cohort 1b: Conditioning Regimen B; Cohort 2a: Conditioning Regimen A; Cohort 2a: Conditioning Regimen B

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• Pregnant or lactating females.
• 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

Sponsors & Collaborators

• Alice Bertaina: lead
• California Institute for Regenerative Medicine (CIRM): collaborator

Study Sites (1)

Lucile Packard Children's Hospital

Palo Alto, California, 94305, United States

RECRUITING

Related Publications (13)

• Dharnidharka VR, Fiorina P, Harmon WE. Kidney transplantation in children. N Engl J Med. 2014 Aug 7;371(6):549-58. doi: 10.1056/NEJMra1314376. No abstract available.

  PMID: 25099579 BACKGROUND

• Poggio ED, Augustine JJ, Arrigain S, Brennan DC, Schold JD. Long-term kidney transplant graft survival-Making progress when most needed. Am J Transplant. 2021 Aug;21(8):2824-2832. doi: 10.1111/ajt.16463. Epub 2021 Feb 8.

  PMID: 33346917 BACKGROUND

• Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL, Shaffer J, Preffer FI, Ding R, Sharma V, Fishman JA, Dey B, Ko DS, Hertl M, Goes NB, Wong W, Williams WW Jr, Colvin RB, Sykes M, Sachs DH. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008 Jan 24;358(4):353-61. doi: 10.1056/NEJMoa071074.

  PMID: 18216355 BACKGROUND

• Kawai T, Sachs DH, Sprangers B, Spitzer TR, Saidman SL, Zorn E, Tolkoff-Rubin N, Preffer F, Crisalli K, Gao B, Wong W, Morris H, LoCascio SA, Sayre P, Shonts B, Williams WW Jr, Smith RN, Colvin RB, Sykes M, Cosimi AB. Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression. Am J Transplant. 2014 Jul;14(7):1599-611. doi: 10.1111/ajt.12731. Epub 2014 Jun 5.

  PMID: 24903438 BACKGROUND

• Kelter R. Bayesian Hodges-Lehmann tests for statistical equivalence in the two-sample setting: Power analysis, type I error rates and equivalence boundary selection in biomedical research. BMC Med Res Methodol. 2021 Aug 17;21(1):171. doi: 10.1186/s12874-021-01341-7.

  PMID: 34404344 BACKGROUND

• Coemans M, Susal C, Dohler B, Anglicheau D, Giral M, Bestard O, Legendre C, Emonds MP, Kuypers D, Molenberghs G, Verbeke G, Naesens M. Analyses of the short- and long-term graft survival after kidney transplantation in Europe between 1986 and 2015. Kidney Int. 2018 Nov;94(5):964-973. doi: 10.1016/j.kint.2018.05.018. Epub 2018 Jul 24.

  PMID: 30049474 BACKGROUND

• Lepeytre F, Dahhou M, Zhang X, Boucquemont J, Sapir-Pichhadze R, Cardinal H, Foster BJ. Association of Sex with Risk of Kidney Graft Failure Differs by Age. J Am Soc Nephrol. 2017 Oct;28(10):3014-3023. doi: 10.1681/ASN.2016121380. Epub 2017 Jun 7.

  PMID: 28592422 BACKGROUND

• Kitchlu A, Dixon S, Dirk JS, Chanchlani R, Vasilevska-Ristovska J, Borges K, Dipchand AI, Ng VL, Hebert D, Solomon M, Michael Paterson J, Gupta S, Joseph Kim S, Nathan PC, Parekh RS. Elevated Risk of Cancer After Solid Organ Transplant in Childhood: A Population-based Cohort Study. Transplantation. 2019 Mar;103(3):588-596. doi: 10.1097/TP.0000000000002378.

  PMID: 30048393 BACKGROUND

• Busque S, Scandling JD, Lowsky R, Shizuru J, Jensen K, Waters J, Wu HH, Sheehan K, Shori A, Choi O, Pham T, Fernandez Vina MA, Hoppe R, Tamaresis J, Lavori P, Engleman EG, Meyer E, Strober S. Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal. Sci Transl Med. 2020 Jan 29;12(528):eaax8863. doi: 10.1126/scitranslmed.aax8863.

  PMID: 31996467 BACKGROUND

• Crompton KE, Elwood N, Kirkland M, Clark P, Novak I, Reddihough D. Feasibility of trialling cord blood stem cell treatments for cerebral palsy in Australia. J Paediatr Child Health. 2014 Jul;50(7):540-4. doi: 10.1111/jpc.12618. Epub 2014 Jun 9.

  PMID: 24909743 BACKGROUND

• Scandling JD, Busque S, Lowsky R, Shizuru J, Shori A, Engleman E, Jensen K, Strober S. Macrochimerism and clinical transplant tolerance. Hum Immunol. 2018 May;79(5):266-271. doi: 10.1016/j.humimm.2018.01.002. Epub 2018 Jan 9.

  PMID: 29330112 BACKGROUND

• Bertaina A, Merli P, Rutella S, Pagliara D, Bernardo ME, Masetti R, Pende D, Falco M, Handgretinger R, Moretta F, Lucarelli B, Brescia LP, Li Pira G, Testi M, Cancrini C, Kabbara N, Carsetti R, Finocchi A, Moretta A, Moretta L, Locatelli F. HLA-haploidentical stem cell transplantation after removal of alphabeta+ T and B cells in children with nonmalignant disorders. Blood. 2014 Jul 31;124(5):822-6. doi: 10.1182/blood-2014-03-563817. Epub 2014 May 28.

  PMID: 24869942 BACKGROUND

• Bertaina A, Grimm PC, Weinberg K, Parkman R, Kristovich KM, Barbarito G, Lippner E, Dhamdhere G, Ramachandran V, Spatz JM, Fathallah-Shaykh S, Atkinson TP, Al-Uzri A, Aubert G, van der Elst K, Green SG, Agarwal R, Slepicka PF, Shah AJ, Roncarolo MG, Gallo A, Concepcion W, Lewis DB. Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia. N Engl J Med. 2022 Jun 16;386(24):2295-2302. doi: 10.1056/NEJMoa2117028.

  PMID: 35704481 BACKGROUND

MeSH Terms

Conditions

Cystinosis; Lupus Nephritis

Interventions

Cyclophosphamide; fludarabine; Whole-Body Irradiation; Rituximab; Melphalan; Kidney Transplantation

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Therapeutics; Investigative Techniques; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Renal Replacement Therapy; Organ Transplantation; Transplantation; Surgical Procedures, Operative; Urologic Surgical Procedures; Urogenital Surgical Procedures

Study Officials

• Alice Bertaina, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

• Paul Grimm, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Model Details: The study has two cohorts (Cohort 1b which will be safety lead-in with 4 patients, and then cohort 2a of 8 patients). The data generated will be compared with historical data available on outcomes of KT performed as SoC in this patient population.

Study Record Dates

• First Submitted: August 17, 2022
• First Posted: August 19, 2022
• Study Start: January 10, 2023
• Primary Completion (Estimated): October 1, 2032
• Study Completion (Estimated): October 1, 2034
• Last Updated: July 17, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)