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

Официальное название

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

Обзор

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.

Вмешательства

• Препарат Cyclophosphamide 1200 mg/Kg
  Cyclophosphamide 1200 mg/Kg will be administered as part of the conditioning regimen A prior to HSCT
• Препарат 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
• Препарат Cyclophosphamide 100 mg/Kg
  Cyclophosphamide 100 mg/Kg will be administered as part of the conditioning regimen B prior to HSCT
• Лучевая терапия Total Body Irradiation
  Total Body Irradiation 200 cGy will be administered as part of the conditioning regimen prior to HSCT
• Препарат ATG
  ATG 7.5 mg/Kg will be administered as part of the conditioning regimen prior to HSCT
• Препарат Rituximab
  Rituximab 200 mg/m2 will be administered within 24 hours of the HSCT
• Препарат Melphalan
  Melphalan 100 mg/m2 will be administered as part of the conditioning regimen prior to HSCT
• Устройство 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
• Процедура 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

Первичные конечные точки

• Number of patients who are able to discontinue immunosuppression post-KT [Срок оценки: Day +90 post-KT]

Вторичные конечные точки (9)

• Number of patients with successful kidney function [Срок оценки: +1 year post-KT]
• Number of patients with myloid engraftment [Срок оценки: Day +42 post-HSCT]
• Number of patients with persistent full donor chimerism [Срок оценки: Day +180 and 1 year post-KT]
• Number of patients with acute GvHD [Срок оценки: Day +90 and Day +180 post-HSCT]
• Number of patients with chronic GvHD [Срок оценки: +1 year post-HSCT]
• Number of patients with de novo acute GVHD [Срок оценки: +1 year post-KT]
• Number of patients with de novo chronic GVHD [Срок оценки: +1 year post-KT]
• Number of patients with functional tolerance to donor cells [Срок оценки: 6- and 12-months post-KT]
• Number of cases of secondary malignancies [Срок оценки: +5 year post-KT]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Lucile Packard Children's Hospital — Palo Alto

Публикации

• 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
• 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
• 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
• 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 PMID 24903438
• 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
• 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
• 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
• 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

Идентификаторы

NCT: NCT05508009 · IRB-65421

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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