Back to results

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

Primary Purpose

SIOD, Cystinosis, FSGS

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Cyclophosphamide 1200 mg/Kg

Fludarabine

Cyclophosphamide 100 mg/Kg

Total Body Irradiation

ATG

Rituximab

Melphalan

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

Kidney Transplant

About this trial

This is an interventional treatment trial for SIOD

Eligibility Criteria

1 Year - 30 Years (Child, Adult)All SexesDoes not accept 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

Sites / Locations

Lucile Packard Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Cohort 1b: Conditioning Regimen A

Cohort 2a: Conditioning Regimen A

Cohort 1b: Conditioning Regimen B

Cohort 2a: Conditioning Regimen B

Arm 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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

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.

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

Number of patients with acute GvHD

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

Number of patients with chronic GvHD

Cumulative incidence of chronic GvHD by NIH consensus criteria

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)

Number of patients with de novo chronic GVHD

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

Number of patients with functional tolerance to donor cells

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

Number of cases of secondary malignancies

New incidence of secondary malignancies in patients after study participation

Full Information

NCT ID

NCT05508009

First Posted

August 17, 2022

Last Updated

July 13, 2023

Sponsor

Alice Bertaina

Collaborators

California Institute for Regenerative Medicine (CIRM)

1. Study Identification

Unique Protocol Identification Number

NCT05508009

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Recruiting

Study Start Date

January 10, 2023 (Actual)

Primary Completion Date

October 2032 (Anticipated)

Study Completion Date

October 2034 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Alice Bertaina

Collaborators

California Institute for Regenerative Medicine (CIRM)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

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)

Allocation

Non-Randomized

Enrollment

12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1b: Conditioning Regimen A

Arm Type

Experimental

Arm Description

Arm Title

Cohort 2a: Conditioning Regimen A

Arm Type

Experimental

Arm 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.

Arm Title

Cohort 1b: Conditioning Regimen B

Arm Type

Experimental

Arm 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.

Arm Title

Cohort 2a: Conditioning Regimen B

Arm Type

Experimental

Arm 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.

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide 1200 mg/Kg

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide 100 mg/Kg

Intervention Description

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

Intervention Type

Radiation

Intervention Name(s)

Total Body Irradiation

Other Intervention Name(s)

TBI

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

ATG

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Rituximab

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Melphalan

Intervention Description

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

Intervention Type

Device

Intervention Name(s)

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

Intervention Description

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.

Intervention Type

Procedure

Intervention Name(s)

Kidney Transplant

Intervention Description

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

Primary Outcome Measure Information:

Title

Number of patients who are able to discontinue immunosuppression post-KT

Description

Donor chimerism equal or greater to 95% after successful HSCT/KT therapy allows for withdrawal of immunosuppressive therapy in patient

Time Frame

Day +90 post-KT

Secondary Outcome Measure Information:

Title

Number of patients with successful kidney function

Description

Time Frame

+1 year post-KT

Title

Number of patients with myloid engraftment

Description

Time Frame

Day +42 post-HSCT

Title

Number of patients with persistent full donor chimerism

Description

Time Frame

Day +180 and 1 year post-KT

Title

Number of patients with acute GvHD

Description

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

Time Frame

Day +90 and Day +180 post-HSCT

Title

Number of patients with chronic GvHD

Description

Cumulative incidence of chronic GvHD by NIH consensus criteria

Time Frame

+1 year post-HSCT

Title

Number of patients with de novo acute GVHD

Description

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

Time Frame

+1 year post-KT

Title

Number of patients with de novo chronic GVHD

Description

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

Time Frame

+1 year post-KT

Title

Number of patients with functional tolerance to donor cells

Description

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

Time Frame

6- and 12-months post-KT

Title

Number of cases of secondary malignancies

Description

New incidence of secondary malignancies in patients after study participation

Time Frame

+5 year post-KT

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Year

Maximum Age & Unit of Time

30 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alice Bertaina, MD

Organizational Affiliation

Stanford University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Paul Grimm, MD

Organizational Affiliation

Stanford University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Lucile Packard Children's Hospital

City

Palo Alto

State/Province

California

ZIP/Postal Code

94305

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

SCGT Clinical Trials Program

Phone

650-723-0912

DL-SCTIntakeCoordinators@stanfordchildrens.org

First Name & Middle Initial & Last Name & Degree

Alice Bertaina, MD

First Name & Middle Initial & Last Name & Degree

Paul Grimm, MD

First Name & Middle Initial & Last Name & Degree

Orly Klein, MD

First Name & Middle Initial & Last Name & Degree

David Shyr, MD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

25099579

Citation

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.

Results Reference

background

PubMed Identifier

33346917

Citation

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.

Results Reference

background

PubMed Identifier

18216355

Citation

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.

Results Reference

background

PubMed Identifier

24903438

Citation

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.

Results Reference

background

PubMed Identifier

34404344

Citation

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.

Results Reference

background

PubMed Identifier

30049474

Citation

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.

Results Reference

background

PubMed Identifier

28592422

Citation

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.

Results Reference

background

PubMed Identifier

30048393

Citation

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.

Results Reference

background

PubMed Identifier

31996467

Citation

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.

Results Reference

background

PubMed Identifier

24909743

Citation

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.

Results Reference

background

PubMed Identifier

29330112

Citation

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.

Results Reference

background

PubMed Identifier

24869942

Citation

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.

Results Reference

background

PubMed Identifier

35704481

Citation

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.

Results Reference

background

Learn more about this trial

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

We'll reach out to this number within 24 hrs