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SIODPhase 1/2NCT05508009

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

A Phase 1/2 study testing Cyclophosphamide 1200 mg/Kg, Fludarabine and Cyclophosphamide 100 mg/Kg in people with SIOD and Cystinosis, run by Alice Bertaina at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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… Read more about this study

Who is it for?
Ages 1 year to 30 years
Conditions the study is for
SIOD, Cystinosis, FSGS
What is being tested?
Cyclophosphamide 1200 mg/Kg, Fludarabine and Cyclophosphamide 100 mg/Kg
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
1 siteUnited States
Study dates
10 Jan 2023to Oct 2034
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 30 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Anticipated need for kidney transplant due to:
  • 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

Who cannot join

  • 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 locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

United States1 site, 1 recruiting

  • Lucile Packard Children's Hospital

    Palo Alto, California, 94305

    SCGT Clinical Trials Program, 650-723-0912, DL-SCTIntakeCoordinators@stanfordchildrens.org

    Alice Bertaina, MD

    Recruiting

Other trials in United States

About this study

Official 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

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.

Being tested
Cyclophosphamide 1200 mg/Kg, Fludarabine, Cyclophosphamide 100 mg/Kg, Total Body Irradiation, ATG
Medical subject headings
Cystinosis, Lupus Nephritis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Cyclophosphamide 1200 mg/KgDrug

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

  • FludarabineDrug

    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/KgDrug

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

  • Total Body IrradiationRadiation

    Also called TBI

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

  • ATGDrug

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

  • RituximabDrug

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

  • MelphalanDrug

    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 SystemDevice

    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 TransplantProcedure or surgery

    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

Study groups in NCT05508009
Study groupRoleWhat they receive
Cohort 1b: Conditioning Regimen AExperimentalAn 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.
Receives: 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 AExperimentalIf 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.
Receives: 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 BExperimentalAn 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.
Receives: 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 BExperimentalIf 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.
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: Day +90 post-KT

Secondary outcomes (9)

  1. Number of patients with successful kidney function

    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.

    Measured: +1 year post-KT

  2. Number of patients with myloid engraftment

    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.

    Measured: Day +42 post-HSCT

  3. Number of patients with persistent full donor chimerism

    >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

    Measured: Day +180 and 1 year post-KT

  4. Number of patients with acute GvHD

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

    Measured: Day +90 and Day +180 post-HSCT

  5. Number of patients with chronic GvHD

    Cumulative incidence of chronic GvHD by NIH consensus criteria

    Measured: +1 year post-HSCT

  6. Number of patients with de novo acute GVHD

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

    Measured: +1 year post-KT

  7. Number of patients with de novo chronic GVHD

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

    Measured: +1 year post-KT

  8. Number of patients with functional tolerance to donor cells

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

    Measured: 6- and 12-months post-KT

  9. Number of cases of secondary malignancies

    New incidence of secondary malignancies in patients after study participation

    Measured: +5 year post-KT

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Aug 2022
  2. Study start10 Jan 2023
  3. Primary completionOct 2032 (estimated)
  4. Study completionOct 2034 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Model description
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.
Masking
None (open label)
Enrolment
12 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05508009
Sponsor's protocol ID
IRB-65421
Status last verified
Jul 2023
First submitted
17 Aug 2022
Last updated
17 Jul 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
Yes
Individual data sharing
No

Publications

  • 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.

    PubMed 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.

    PubMed 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.

    PubMed 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: 10.1111/ajt.12731. Epub 2014 Jun 5.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 30048393

  • 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.

    PubMed 31996467

  • 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.

    PubMed 24909743

  • 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.

    PubMed 29330112

  • 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.

    PubMed 24869942

  • 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.

    PubMed 35704481

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Cyclophosphamide 1200 mg/Kg, Fludarabine and Cyclophosphamide 100 mg/Kg in people with SIOD and Cystinosis, run by Alice Bertaina at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 17 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of patients who are able to discontinue immunosuppression post-KT (time frame: Day +90 post-KT). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05508009, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jul 2023.

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